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The relationship among inflammation, pain, and cognitive decline in osteoarthritis (OA) patients is complex and has not been sufficiently explored; therefore, we undertook this research to evaluate how OA-related inflammation and pain affect cognitive functions, as well as to examine the potential of urinary markers as indicators of these conditions. This study examined fifty OA patients through clinical and cognitive assessments, morphological analyses, urinary biomarkers, and bioinformatics. Morphologically, 24% of patients had moderate to high synovial inflammation, which was significantly correlated with depressive symptoms, pain intensity, and self-reported anxiety. The Montreal Cognitive Assessment indicated minimal decline in most patients but showed negative correlations with age and inflammation severity. Urinary TNF-α and TGF-β1 levels positively correlated with body mass index and pain and synovitis score and immune cell infiltration, respectively. In contrast, cartilage oligomeric matrix protein and C-telopeptides of type II collagen showed inverse correlations with pain duration and cognitive function, respectively. Distinct patient clusters with higher inflammation were identified and were associated with reported pain and depressive symptoms. Urinary TNF-α and TGF-β1 can serve as biomarkers reflecting inflammation and disease severity in OA. This study suggests that synovial inflammation may be linked to mental and cognitive health in some patient cohorts.

Background: The early and accurate diagnosis of preeclampsia is crucial to avoid serious complications for both the mother and baby. However, the current diagnostic methods are limited, and there is a need for new diagnostic biomarkers. Previous studies have shown that cathepsin D (CTD) participates in the pathophysiology of preeclampsia and is present in urine samples, making it a potential biomarker for the disease. This study aimed to compare urinary and serum levels of CTD in preeclamptic and normotensive women and analyze its potential role as a diagnostic biomarker in preeclampsia., Methods: The study included thirty-nine patients with preeclampsia and twelve normotensive pregnant women as controls. Biomarkers were determined using Multiplex Assay kit, and serum prolactin (Prl) and urinary TNF-α levels were also evaluated. Statistical analysis was conducted using the Mann-Whitney U test., Results: We found that urinary and serum CTD levels were significantly higher in the preeclampsia group than in the normotensive group, suggesting that CTD could be a diagnostic biomarker for preeclampsia. No significant differences were found in the levels of serum prolactin or urinary TNF-α between the two groups., Conclusions: The study provides evidence that non-invasive biological samples such as urine can be used to improve new therapeutic strategies for the early management of preeclampsia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Aims: Interleukin-9 (IL-9) attenuates podocyte injury in experimental kidney disease, but its role in diabetic nephropathy is unknown. We sought to relate urinary IL-9 levels to the release of podocyte-derived extracellular vesicles (EVs) in youth with type 1 diabetes. We related urinary IL-9 levels to clinical variables and studied interactions between urinary IL-9, vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) on urinary albumin/creatinine ratio (ACR) a functional measure of podocyte injury., Methods: We performed an analysis of urine samples and clinical data from a cohort of youth with type 1 diabetes (n = 53). Cytokines were measured using a Luminex platform (Eve Technologies), and nanoscale flow cytometry was employed to quantify urinary podocyte-derived EVs. All urinary measures were normalized to urinary creatinine., Results: Mean age was 14.7 ± 1.6 years, and the mean time from diagnosis was 6.7 ± 2.9 years. Mean HbA1c was 70.3 ± 13.9 mmol/mol, mean ACR was 1.3 ± 1.9 mg/mmol, and mean eGFR was 140.3 ± 32.6 ml/min/1.73 m 2 . IL-9 was inversely related to podocyte EVs (r = - 0.56, p = 0.003). IL-9 was also inversely related to blood glucose, HbA1C and eGFR (r = - 0.44, p = 0.002; r = - 0.41, p = 0.003; r = - 0.49, p < 0.001, respectively) and positively correlated with systolic BP (r = 0.30, p = 0.04). There was a significant interaction between IL-9, EVs and ACR (p = 0.0143), and the relationship between IL-9 and ACR depended on VEGF (p = 0.0083), TNFα (p = 0.0231) and IL-6 levels (p = 0.0178)., Conclusions: IL-9 is associated with podocyte injury in early type 1 diabetes, and there are complex interactions between urinary IL-9, inflammatory cytokines and ACR., (© 2022. The Author(s).)

Background: We previously demonstrated that urine interleukin (IL)-9 and tumor necrosis factor (TNF)-α can distinguish acute interstitial nephritis (AIN) from other causes of acute kidney injury. Here we evaluated the role of these biomarkers to prognosticate kidney function in patients with AIN., Methods: In a cohort of participants with biopsy-proven, adjudicated AIN, we tested the association of histological features and urine biomarkers (IL-9 and TNF-α) with estimated glomerular filtration rate measured 6 months after diagnosis (6 m-eGFR) controlling for eGFR before AIN and albuminuria. We also evaluated subgroups in whom corticosteroid use was associated with 6 m-eGFR., Results: In the 51 (93%) of the 55 participants with complete data, median (interquartile range) eGFR before and 6 m after AIN were 41 (27-69) and 28 (13-47) mL/min/1.73 m2, respectively. Patients with higher severity of interstitial fibrosis had lower 6 m-eGFR, whereas those with higher tubulointerstitial infiltrate had higher 6 m-eGFR. IL-9 levels were associated with lower 6 m-eGFR only in the subset of patients who did not receive corticosteroids [6m-eGFR per doubling of IL-9, -6.0 (-9.4 to -2.6) mL/min/1.73 m2]. Corticosteroid use was associated with higher 6 m-eGFR [20.9 (0.2, 41.6) mL/min/1.73 m2] only in those with urine IL-9 above the median (>0.66 ng/g) but not in others., Conclusions: Urine IL-9 was associated with lower 6 m-eGFR only in participants not treated with corticosteroids. Corticosteroid use was associated with higher 6 m-eGFR in those with high urine IL-9. These findings provide a framework for IL-9-guided clinical trials to test efficacy of immunosuppressive therapy in patients with AIN., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: The health effects of heavy solid fuel use in winter in rural China are of concern. The effects of air pollution resulting from domestic solid fuel combustion in rural households on rural homemakers' biomarkers were revealed in this study., Methods: In total, 75 female homemakers from rural areas of Guanzhong Basin, the Fenwei Plain, People's Republic of China, were randomly selected and divided into three groups (biomass users, coal users, and nonusers of solid fuel user [control group]). The differences in biological indicators, including 8-hydrox-2'-deoxyguanosine (8-OHdG), interlukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) in urine samples as well as blood pressure (BP, including systolic BP [SBP] and diastolic BP [DBP]) and heart rate (HR) among the groups in winter and summer were investigated using statistical analysis., Results: IL-6, 8-OHdG, HR, SBP, and DBP were significantly higher in winter than in summer (P < 0.05) owing to the poor air quality resulted from the excessive use of solid fuels in winter. Significant seasonal differences in 8-OHdG were observed for both coal and biomass users. After the influence of confounders was removed, only IL-6 levels in the urine of solid fuel users were significantly higher than that of the control group., Conclusions: IL-6 is a sensitive biomarker representing inflammatory responses to particulate matter emitted through household solid fuel combustion. Locally, excessive use of solid fuels in winter posed serious PM 2.5 pollution in this area and adverse effects on inflammatory biomarkers in these rural homemakers and induced DNA damage related to oxidative stress., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Chronic kidney disease (CKD) in children, despite the progress in science and technology, is still a serious challenge. Early CKD detection gives a chance of early therapeutic intervention and lowering the progression of the disease. According to several publications indicating the possible use of alpha-Klotho (αKL) and tumour necrosis factor alpha (TNFα) for the early detection of the disease in adults, an attempt was made to evaluate their usefulness in the paediatric population., Material and Methods: The study group consisted of 42 patients with CKD with a mean age of 10.7 years (18 girls and 24 boys). The control group involved 21 healthy children with a mean age of 8.4 years (11 girls and 10 boys). Anthropometrical parameters and blood pressure were taken and routine biochemical tests were performed in the whole group. The concentrations of TNFα and αKL in serum and urine were determined by enzyme immunoassay., Results: Children from the CKD group showed a statistically significant difference in serum TNFα and αKL in comparison to the control group. There was no significant relationship between the evaluated markers and sex, presence of hypertension, or proteinuria in the children. The mean αKL serum concentration was higher in patients on dialysis compared to the group of conservatively treated children, whereas the values of TNFα in serum and urine, as well as the αKL in urine, did not differ significantly in these groups. A significant positive correlation was found between serum αKL concentration and serum creatinine, but there was no other correlation between serum αKL or TNFα concentration and any of the measured anthropometric and laboratory parameters., Conclusions: Serum TNFα and αKL levels in children with chronic kidney disease, although being statistically different compared to the group of healthy children, except for the correlation of serum aKL and creatinine, showed no other correlations to the most parameters used for chronic kidney disease evaluation including, eGFR. Their usefulness in the early detection of kidney dysfunction in children was not proven.

Background: Long-chain n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may alter oxidative status and immune function after exercise. The aim of this pilot study was to determine the probable association between n-3 supplementation and physical exercise, observing the variations in markers of oxidative stress and inflammation., Methods: Thirty-nine subjects of both sexes aged 17-30 years were divided into two groups: 1) (n = 21) trained Athletes; 2) (n = 18) Sedentary subjects. All subjects were given about 4 g/day of n-3 supplementation, rich in EPA and DHA, for 8 weeks. Blood, saliva and urine samples were collected pre- (T0) and post- (T1) supplementation. Hematological parameters (tryglicerides, total cholesterol, HDL, CPK, LDH, HGH, IGF-1), oxidative markers (MDA, 8-OHdG, PCc), antioxidant parameters (GPx, SOD, CAT, DPPH scavenger), exercise-induced stress markers (testosterone and cortisol) and an inflammatory marker (TNF-α) were measured. All tests were two-sided and a p-value of less than 0.05 was considered as statistically significant., Results: The results showed that MDA and TNF-αmean values significantly decreased after supplementation in both Athletes and Sedentary subjects: variation was greater in Athletes than in Sedentary control subjects. Generally, our results suggested that supplementation with n-3 PUFAs created a synergic variation in the parameters from a baseline state (T0) to a treated state after supplementation (T1), in terms of size and modality, which was significantly different in Athletes compared to Sedentary subjects., Conclusion: In conclusion, supplementation with about 4 g/day of n-3 PUFAs, rich in EPA and DHA, for 8 weeks, seemed to be effective in counteracting some parameters involved in oxidative stress and inflammation, induced by acute strenuous physical exercise.

Carbohydrate-restricted diets are increasingly recognized as options for dietary management of type 2 diabetes mellitus (T2DM). We investigated the effects of a carbohydrate-reduced high-protein (CRHP) and a conventional diabetes (CD) diet on oxidative stress and inflammation in weight stable individuals with T2DM. We hypothesized that the CRHP diet would improve markers of oxidatively generated RNA and DNA modifications as well as inflammatory parameters. Thirty participants with T2DM were randomized to 6 weeks of CRHP or CD dietary treatment (30/50 energy percentage (E%) carbohydrate, 30/17E% protein, 40/33E% fat), followed by a cross-over to the opposite diet for a subsequent 6-week period. All meals were provided during the study and body weight was controlled. Diurnal urine samples were collected after 4 weeks on each diet and oxidatively generated RNA and DNA modifications were measured as 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Fasting concentrations of soluble urokinase plasminogen activator receptor, high-sensitivity C-reactive protein, tumor necrosis factor alpha and interleukin-6 were measured before and after 6 weeks of interventions. Compared with the CD diet, the CRHP diet increased 24-hour urinary excretion of 8-oxoGuo by 9.3% (38.6 ± 12.6 vs. 35.3 ± 11.0 nmol/24 h, p =  .03), whereas 8-oxodG did not differ between diets (24.0 ± 9.5 vs. 24.8 ± 11.1 nmol/24 h, p  = .17). Changes in plasma inflammatory parameters did not differ between CRHP and CD diets, all p ≥  .2. The clinical implications of increased RNA oxidation following a CRHP diet as well as long-term effects of carbohydrate-restriction on markers of oxidatively generated nucleic acid modifications should be a field of future study.

Urinary tract infection (UTI) is common among pediatric population. Pyelonephritis, especially in young infants, is associated with a significant morbidity. Usually, clinical manifestations, laboratory findings, and imaging are used to differentiate between lower and upper UTI. Lack of specific clinical findings and commonly used nonspecific blood indices are important hamper differentiation between lower and upper UTI in early stages. Imaging techniques are neither cost benefit nor safe for detection of UTI. Recent efforts have focused on characterization of novel serum and urinary biomarkers for early detection of acute pyelonephritis in children. It seems that urinary NGAL, NAG, TNF-α and IL-8 may be used as novel markers for early diagnosis of acute pyelonephritis in children.

Background: This study investigated the association between urinary levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-α) with estimated glomerular filtration rate (eGFR), urinary albumin/creatinine ratio (uACR), and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in patients with type 2 diabetes (T2D)., Methods: Urinary concentrations of IL-6, IL-10, TNF-α, ACR, and NGAL were measured in 121 patients with T2D., Results: Urinary IL-6 and TNF-α increased 45.5% and 49.4% in the highest uACR quartile compared to lowest quartile. Urinary IL-10 levels decreased 40.9% in the highest uACR quartile compared to the lowest quartile. Urinary IL-6 and TNF-α were 75.3% and 81.6%, higher in the highest uNGAL quartile compared to the lowest quartile. Urinary IL-10 concentration was 69.8% lower in patients from the highest uNGAL quartile compared to lowest quartile., Conclusions: Urinary IL-6, IL-10, and TNF-α were associated with indicators of glomerular and tubular injuries in patients with T2D.

Background: The aim of this study was to investigate the expression of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) in expressed prostatic secretions (EPSs) of patients with chronic prostatitis (CP) and the expression of prostatic exosomal protein (PSEP) in urine, and to evaluate its correlation with the condition., Methods: Urine samples from 310 patients with CP (101 National Institutes of Health [NIH] II, 112 NIH IIIa, and 97 NIH IIIb, classified according to the US National Institutes of Health) and 110 control group subjects were collected. The samples were tested for PSEP by enzyme-linked immunosorbent assay (ELISA). At the same time, EPSs in 60 patients from 310 patients with CP and 20 control group subjects were collected. The levels of IL-10 and TNF-α in the collected samples that EPS were determined by double antibody sandwich ELISA. SPSS 23.0 statistical software was used for statistical analysis of the measured data., Results: The level of PSEP in patients with CP was significantly higher than that in the control group (P < .001). The levels of TNF-α and IL-10 in the EPS of patients with NIH II and NIH IIIa CP were higher than those of the patients with NIH IIIb and the control group (P < .001). There was a positive correlation between PSEP and IL-10 and TNF-α, while TNF-α and IL-10 were also positively correlated., Conclusion: PSEP, TNF-α, and IL-10 may serve as a basis for the classification diagnosis of CP. Their combination can provide more accurate diagnostic information for clinical CP typing.

Due to their high aspect ratio and increased surface-to-foot-print area, arrays of vertical semiconductor nanowires are used in numerous biological applications, such as cell transfection and biosensing. Here we focus on two specific valuable biosensing approaches that, so far, have received relatively limited attention in terms of their potential capabilities: cellular mechanosensing and lightguiding-induced enhanced fluorescence detection. Although proposed a decade ago, these two applications for using vertical nanowire arrays have only very recently achieved significant breakthroughs, both in terms of understanding their fundamental phenomena, and in the ease of their implementation. We review the status of the field in these areas and describe significant findings and potential future directions.

BACKGROUNDClinical diagnosis of acute interstitial nephritis (AIN) is challenging because of lack of a diagnostic biomarker and requires a kidney biopsy. We hypothesized that AIN is mediated by specific T cell subsets such that specific T cell cytokine levels could serve as biomarkers to distinguish AIN from other causes of acute kidney disease (AKD).METHODSWe enrolled consecutive sampling participants who underwent a kidney biopsy for AKD evaluation at 2 centers between 2015 and 2018. Three pathologists independently established AIN diagnosis through review of kidney biopsies. Through univariable and multivariable analysis of 12 selected urine and plasma cytokines, we identified 2 that were diagnostic of AIN.RESULTSOf the 218 participants, 32 (15%) were diagnosed with AIN by all 3 pathologists. Participants with AIN had consistently higher levels of urine TNF-α and IL-9 than those with other diagnoses, including acute tubular injury, glomerular diseases, and diabetic kidney disease, and those without any kidney disease. As compared with participants in the lowest quartile, we noted higher odds of AIN in participants in the highest quartiles of TNF-α levels (adjusted odds ratio, 10.9 [1.8, 65.9]) and IL-9 levels (7.5 [1.2, 45.7]) when controlling for blood eosinophils, leukocyturia, and proteinuria. Addition of biomarkers improved area under receiver operating characteristic curve over clinicians' prebiopsy diagnosis (0.84 [0.78, 0.91]) vs. 0.62 [(0.53, 0.71]) and a model of current tests (0.84 [0.76, 0.91] vs. 0.69 [0.58, 0.80]).CONCLUSIONSInclusion of urinary TNF-α and IL-9 improves discrimination over clinicians' prebiopsy diagnosis and currently available tests for AIN diagnosis.FUNDINGSupported by NIH awards K23DK117065, T32DK007276, K24DK090203, K23DK097201, R01DK113191, UG3-DK114866, P30DK079310; the Robert E. Leet and Clara Guthrie Patterson Trust; and American Heart Association award 18CDA34060118.

Arterial hypertension is considered to be an inflammatory condition with low intensity. Therefore, an elevated concentration of inflammatory cytokines can be expected in patients with systemic arterial hypertension, including tumor necrosis factor (TNF).The study included a group of 96 persons aged 18 to 65 years: 76 patients with primary arterial hypertension and 20 healthy individuals (control group). Blood pressure was measured in all individuals using the office and ambulatory blood pressure monitoring (ABPM) measurement, blood was collected for laboratory tests [tumor necrosis factor (TNF), tumor necrosis factor receptor 1 (TNFR1)], and 24-hour urine collection was performed in which albuminuria and TNF concentration were assessed. Moreover, assessment of the intima-media thickness (IMT) in ultrasonography and left ventricular mass index (LVMI) in echocardiography were carried out.Statistically elevated TNF concentration in the blood serum (P = .0001) and in the 24-hour urine collection (P = .0087) was determined in patients with hypertension in comparison with the control group. The TNF and TNFR1 concentration in the serum and TNF in the 24-hour urine in the group of patients with arterial hypertension and organ damages and without such complications did not differ statistically significantly.We observed a positive and statistically significant correlation between TNFR1 concentration in the serum and TNF urine excretion in patients with hypertension (r = 0.369, P < .05)Patients with arterial hypertension are characterized by higher TNF concentrations in blood serum and higher TNF excretion in 24-hour urine than healthy persons.TNF and TNFR1 concentration in blood serum and TNF excretion in 24-hour urine in patients with early organ damages due to arterial hypertension do not differ significantly from those parameters in patients with arterial hypertension without organ complications.There is a positive correlation between TNFR1 concentration in the serum and TNF urine excretion in patients with hypertension.

Background: Uric acid presents different roles in an organism. High serum uric acid concentrations may induce inflammatory pathways and promote kidney damage through different mechanisms. Therefore, this study investigated the association among high serum uric acid concentrations, renal tubular damage, and renal inflammation assessed via estimation of urinary kidney injury molecule-1 (KIM-1) and inflammatory cytokines in patients with type 2 diabetes (T2D)., Methods: Urinary concentrations of KIM-1, IL-1, IL-6, IL-10, and TNF-alpha, as well as other biochemical parameters, were assessed in 125 patients with T2D who were grouped into two groups based on the serum uric acid levels (<6.0 mg/dL and ≥6.0 mg/dL). Patients were also stratified according to the tertiles of serum uric acid concentrations., Results: Urinary KIM-1, IL-1, IL-6, and TNF-alpha were higher in patients with serum uric acid concentrations ≥ 6.0 mg/dL. However, the differences between the groups were not statistically significant when the urinary values of KIM-1 and cytokines were normalized by the urinary creatinine concentration. Serum uric acid concentrations were significantly associated with urinary KIM-1 (values normalized by urinary creatinine concentration) and urinary TNF-alpha (absolute values and values normalized by urinary creatinine concentration), independent of the body mass index (BMI) and estimated glomerular filtration rate (eGFR)., Conclusions: High serum uric acid concentrations were associated with high urinary KIM-1 levels accompanied by the increase of urinary proinflammatory cytokines in patients with T2D. However, normalization of urinary markers by urine creatinine concentration seems to influence the profile of the results.

Objective: To evaluate the relationship between the inflammatory profile and mood states in the different phases of the menstrual cycle in soccer players with and without premenstrual syndrome (PMS)., Methods: Data on the menstrual cycle and mood states were collected using the Daily Symptom Report and the Brunel Mood Scale. Cytokine and stress hormone concentrations were measured in urine by flow cytometry before and after a game in the luteal phase and in the follicular phase of one menstrual cycle., Results: In all, 59.6% of the athletes had PMS. The PMS group showed higher concentrations of interleukin (IL)-1β, IL-6, and IL-8 than the athletes without PMS. After the game, IL-6 decreased in the follicular phase and the luteal phase. The tumor necrosis factor-α levels were higher in the group without PMS during the post-game follicular phase than before the game. In the PMS group, tension was higher in the follicular phase before the game and depression was higher in the pre-game luteal phase than in the group without PMS. The PMS group also presented a negative correlation between depression and IL-10 levels in the pre-game follicular phase. Finally, in the pre-game luteal phase were found positive correlations between growth hormone and IL-10., Conclusion: PMS influences the inflammatory condition related to mood states and stress hormones in female soccer players., (© 2019 S. Karger AG, Basel.)

Objectives: Allograft rejection is an important cause of early and long-term graft loss in kidney transplant recipients. Tumor necrosis factor-alpha promotes T-cell activation, the key reaction leading to allograft rejection. Here, we investigated whether serum and urinary tumor necrosis factor-alpha levels can predict allograft rejection., Materials and Methods: This study included 65 living related-donor renal transplant recipients with mean follow-up of 26 ± 9 months. Serum and urinary tumor necrosis factor-alpha levels were measured at pretransplant and at posttransplant time points (days 1 and 7 and months 3 and 6); serum creatinine levels were also monitored during posttransplant follow-up. Standard enzyme-linked immunoabsorbent assay was used to detect tumor necrosis factor-alpha levels. Clinical variables were monitored., Results: Nine of 65 patients (13.8%) had biopsy-proven rejection during follow-up. Preoperative serum and urinary tumor necrosis factor-alpha levels were not significantly different when we compared patients with and without rejection. Serum tumor necrosis factor-alpha levels (in pg/mL) were significantly higher in the allograft rejection versus nonrejection group at day 7 (11.5 ± 4.7 vs 15.4 ± 5.8; P = .029) and month 1 (11.1 ± 4.8 vs 17.8 ± 10.9; P =.003). Urinary tumor necrosis factor-alpha levels (in pg/mL) were also elevated in the allograft rejection versus the nonrejection group at days 1 (10.2 ± 2.5 vs 14.1 ± 6.8; P = .002) and 7 (9.8 ± 2.2 vs 14.5 ± 2.7; P < .001) and at months 1 (8.0 ± 1.7 vs 11.8 ± 2.4; P < .001), 3 (7.7 ± 1.6 vs 9.6 ± 1.7; P = .002), and 6 (7.4 ± 1.6 vs 8.9 ± 0.9; P = .005)., Conclusions: Our preliminary findings suggest that tumor necrosis factor-alpha has a role in diagnosing renal transplant rejection. Serum and urinary tumor necrosis factor-alpha levels may be a possible predictor for allograft rejection.

Emerging studies suggest that lipid accumulates in the kidneys during diabetic kidney disease (DKD). However, the correlation between ectopic lipid accumulation with tubular damage has not been thoroughly elucidated to date. Using Oil Red staining, lipid accumulation was observed in the kidneys of type 2 DKD patients (classes II-III) and db/db mice compared with the control and was predominantly located in the proximal tubular compartment. Immunohistochemistry (IHC) staining showed that the intensity of adipose differentiation related protein (ADRP) and sterol regulatory element binding protein-1 (SREBP-1) was clearly up-regulated, which was positively correlated with the tubulointerstitial damage score and inflammation. Furthermore, the urine ADRP content significantly increased in DKD patients compared with the control, which positively correlated with abnormal lipid metabolism, serum creatinine, urine N-acetyl-β-glucosaminidase (NAG), albumin excretion (albumin-to-creatinine ratio (ACR)), and tumor necrosis factor-α (TNF-α) expression. However, there was no significant difference observed in plasma ADRP levels. In addition, the expression of SREBP-1 protein was dramatically increased in peripheral blood mononuclear cells (PBMCs) isolated from DKD patients, which was also tightly correlated with urine NAG, ACR, and TNF-α levels. In vitro studies demonstrated increased ADRP and SREBP-1 expression accompanied by lipid accumulation in HK-2 cells cultured in high glucose (HG). HG induced high levels of TNF-α expression, which was partially blocked by transfection of ADRP siRNA or SREBP-1 siRNA. These data indicated that ADRP and SREBP-1 are crucial factors that mediate lipid accumulation with tubular damage and inflammation in DKD, and ectopic lipid accumulation may serve as a novel therapeutic target for amelioration of tubular injury in DKD., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Objective: The effect of pentoxifylline on Klotho levels in patients with type 2 diabetes mellitus with chronic kidney disease (CKD) was assessed in a post hoc analysis of the Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) trial., Research Design and Methods: Circulating and urinary tumor necrosis factor-α (TNF-α) and Klotho were measured before and after 1 year of pentoxifylline. The effect on Klotho expression was assessed in cultured renal tubular cells., Results: Pentoxifylline administration resulted in decreased serum and urinary TNF-α, whereas serum and urinary Klotho increased significantly. Changes in urinary Klotho, urinary TNF-α, and phosphorus were associated with changes in serum Klotho; changes in estimated glomerular filtration rate, urinary TNF-α, and albuminuria were related to urinary Klotho variation. In renal tubular cells, pentoxifylline prevented the decrease in Klotho expression induced by inflammatory cytokines or albumin., Conclusions: Pentoxifylline increased Klotho levels in patients with diabetes with stage 3-4 CKD and prevented reduced Klotho expression in vitro. This beneficial effect may be related to anti-inflammatory and antialbuminuric activity., (© 2018 by the American Diabetes Association.)

Background/aims: The aim of this study was to investigate the therapeutic effect of different doses of tripterygium glycosides (TG) in the treatment of diabetic nephropathy (DN). The effect of TG on blood lipids and safety were also evaluated., Methods: Sixty patients with type 2 DN were randomly divided into three groups (n=20 per group): low-dose (30 mg/day TG), double-dose (60 mg/day TG) and control (placebo) groups, all three times daily for 6 months. The levels of triglycerides, total cholesterol, urinary protein, plasma albumin and serum tumour necrosis factor (TNF)-α were compared between the three groups., Results: After treatment, urinary protein and TNF-α level significantly decreased in patients in the treatment groups, compared with the control group. This decrease was significantly larger in the double-dose group than in the low-dose group. However, there was no significant decrease in triglycerides and total cholesterol in the two treatment groups. Furthermore, plasma albumin was lower in the treatment groups than in the control group., Conclusion: The double dose of TG has improved clinical efficacy, compared with the low dose, and the same safety profile., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

The high specific gravity in the structure of morbidity in children of all age groups, complicated course, determines the urgency of studying the clinical and diagnostic aspects of community-acquired pneumonia. In recent years, interest has been growing in the study of the child's cytokine status. A number of studies indicate that cytokines regulate the severity and duration of the inflammatory process. In this regard, the study of the possibility of determining the level of proinflammatory cytokines (IL-6 , TNF-α) is of great practical importance for assessing the prognosis of community-acquired pneumonia in children. In a prospective cohort study, 90 children with community-acquired pneumonia aged between 5 and 14 years were treated under treatment in the department respiratory of the Children›s Hospital in Karaganda, of which 47% were girls (95% CI 31.51% - 56.33%) and boys 53% (CI 95% 34.91% - 59.88%). The control group included 20 healthy children. Analysis of the results of the study revealed an increase in the content of proinflammatory cytokines in the blood serum and urine on children with community-acquired pneumonia depending on the severity of the course. At the same time, the equivalence of the cytokine trends in serum and urine determines the possibility of noninvasive detection of cytokines, both for characterizing the inflammatory response of the organism as such and for predicting the development of community-acquired pneumonia, which is especially valuable in pediatric practice.

Objective: To identify the inflammatory mediators around the time of pneumonia onset associated with concurrent or later onset of pressure ulcers (PUs)., Design: Retrospective., Setting: Acute hospitalization and inpatient rehabilitation unit of a university medical center., Participants: Individuals (N=86) with traumatic spinal cord injury (SCI) were included in the initial analyses. Fifteen of the 86 developed pneumonia and had inflammatory mediator data available. Of these 15, 7 developed PUs and 8 did not., Interventions: Not applicable., Main Outcome Measures: Twenty-three inflammatory mediators in plasma and urine were assayed. The differences in concentrations of plasma and urine inflammatory mediators between the closest time point before and after the diagnosis of pneumonia were calculated., Results: Initial chi-square analysis revealed a significant (P=.02) association between pneumonia and PUs. Individuals with SCI and diagnosed pneumonia had nearly double the risk for developing PUs compared with those with no pneumonia. In individuals with pneumonia, Mann-Whitney U exact tests suggested an association (P<.05) between the formation of a first PU and a slight increase in plasma concentrations of tumor necrosis factor-alpha (TNF-α), and a decrease in urine concentrations of TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-15 after onset of pneumonia., Conclusions: These findings suggest that a relatively small increase in plasma TNF-α, and decreases in urine TNF-α, GM-CSF, and IL-15 from just before to just after the diagnosis of pneumonia could be markers for an increased risk of PUs in individuals with pneumonia after traumatic SCI., (Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate the role of inflammatory/lipid markers and potential risk factors for diabetic retinopathy (DR) development in newly diagnosed patients with type 2 diabetes mellitus (T2DM)., Methods: Participants in this study were 1062 patients with newly diagnosed T2DM. Demographic and clinical data of patients were collected. Assessment of DR status was performed using digital two-field photography. In addition, HbA1c (%), lipid profile, and urinary albumin were measured at recruitment. The following inflammatory markers were also measured: serum C-reactive protein, white blood cells, platelet, adiponectin, IL-4, IL-6, IL-10, vascular endothelial growth factor, tumor necrosis factor-α (TNF-α), IL-1b, IL-1 receptor antagonist (IL-1RA), and monocyte chemotactic protein-1. Univariate and multivariate analyses of the association of various potential risk factors and DR were conducted., Results: Univariate analysis showed that male sex, any cardiovascular event, and HbA1c were positively associated with DR, while IL-1RA, IL-1b, IL-6, and TNF-α were significantly negatively associated with presence of DR in the cohort. Risk factors that remained significantly associated with DR presence at the multivariate analysis were male sex, any cardiovascular event, HbA1c, and IL-1RA., Conclusions: Our study demonstrated that HbA1c levels, male sex, and previous cardiovascular events were risk factors for presence of DR in people with newly diagnosed T2DM, while IL-1RA seemed to have a protective role. The prevalence of DR in our population was 20.2%, reflecting current practice. Our findings may contribute to future risk-based modelling of screening for DR.

Background/aims: The diagnosis of type 2 diabetic nephropathy (T2DN) patients is important to prevent the long-term damaging effects of kidney loss in patients with diabetes and is decisive for patient outcomes. The aim of this study was to explore urine retinol binding protein (RBP) and neutrophil gelatinase-associated lipocalin (NGAL) in T2DN patients with and without albuminuria., Methods: A total of 293 T2DN patients were divided into three groups according to their urine albumin/urine creatinine ratio (UACR): normoalbuminuria group (UACR<30 mg/g, n=100), microalbuminuria group (UACR 30-300 mg/g, n=100) and macroalbuminuria group (UACR>300 mg/g, n=93); 50 non-diabetic subjects were recruited as the control group. The levels of urine RBP, NGAL, TNF-α and IL-18 in T2DN patients and non-diabetic subjects were measured using ELISA assays., Results: We first analyzed the clinical characteristics of the control and T2DN groups and found that urine NGAL, RBP, TNF-α and IL-18 levels were significantly increased and significantly correlated with the degree of albuminuria. In addition, univariate linear regression analysis showed that urine RBP was associated with UACR, BMI, Scr, BUN, TG, disease duration, SBP, NGAL, TNF-α and IL-18 levels, and urine NGAL was positively correlated with UACR, Scr, BUN, RBP, TNF-α and IL-18 levels., Conclusion: The results indicate that urine levels of NGAL and RBP may be independently associated with albuminuria in T2DN and may serve as novel biomarkers for the identification of T2DN., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

The aim of the present study was to investigate the association between the presence of albuminuria and cytokines profile with biomarkers of endothelial damage and oxidative stress in patients with type 1 diabetes mellitus (DM1). The sample was composed by 35 healthy individuals, 63 DM1 patients with normoalbuminuria (<30 mg of albumin/g of creatinine) and 62 DM1 patients with micro- and macroalbuminuria (≥30 mg of albumin/g of creatinine). Plasma and urinary cytokines (TNF-α, IL-6 and IL-10) and thrombomodulin levels were determined by ELISA. Oxidative status was evaluated using the TBARS and MTT assays. Diabetic patients were characterized by elevated levels of urinary cytokines TNF-α, IL-6 and IL-10. Those with macroalbuminuria presented significantly higher TNF-α and IL-10 urinary levels when compared to other groups. Urinary and plasmatic levels of TNF-α were positively correlated with plasma levels of cystatin C, creatinine, urea and albuminuria, while they were negatively correlated with estimated glomerular filtration rate. Urinary IL-10 levels proved positive correlation with fasting glucose, HbA1c, thrombomodulin and TBARS, while IL-6 plasma levels were positively correlated with HbA1c and albuminuria. Only urinary TNF-α levels were associated with the presence and severity of macroalbuminuria, after logistic regression analysis. This finding suggests that measurement of urinary TNF-α level may be helpful to evaluate progression to nephropathy in DM1 patients.

Determining ultratrace amounts of protein biomarkers in patient samples in a straightforward and quantitative manner is extremely important for early disease diagnosis and treatment. Here, we successfully demonstrate the novel use of zinc oxide nanorods (ZnO NRs) in the ultrasensitive and quantitative detection of two acute kidney injury (AKI)-related protein biomarkers, tumor necrosis factor (TNF)-α and interleukin (IL)-8, directly from patient samples. We first validate the ZnO NRs-based IL-8 results via comparison with those obtained from using a conventional enzyme-linked immunosorbent method in samples from 38 individuals. We further assess the full detection capability of the ZnO NRs-based technique by quantifying TNF-α, whose levels in human urine are often below the detection limits of conventional methods. Using the ZnO NR platforms, we determine the TNF-α concentrations of all 46 patient samples tested, down to the fg per mL level. Subsequently, we screen for TNF-α levels in approximately 50 additional samples collected from different patient groups in order to demonstrate a potential use of the ZnO NRs-based assay in assessing cytokine levels useful for further clinical monitoring. Our research efforts demonstrate that ZnO NRs can be straightforwardly employed in the rapid, ultrasensitive, quantitative, and simultaneous detection of multiple AKI-related biomarkers directly in patient urine samples, providing an unparalleled detection capability beyond those of conventional analysis methods. Additional key advantages of the ZnO NRs-based approach include a fast detection speed, low-volume assay condition, multiplexing ability, and easy automation/integration capability to existing fluorescence instrumentation. Therefore, we anticipate that our ZnO NRs-based detection method will be highly beneficial for overcoming the frequent challenges in early biomarker development and treatment assessment, pertaining to the facile and ultrasensitive quantification of hard-to-trace biomolecules.

Unlabelled: The response of non-muscle-invasive bladder cancer (NMIBC) to intravesical immunotherapy with bacillus Calmette-Guérin (BCG) depends on adequate stimulation of an immune response. Although BCG has been used for decades, we lack tools to accurately predict response in individual patients. To address this deficiency, we initiated a clinical trial in patients with intermediate- and high-risk NMIBC. BCG was administered according to the Southwest Oncology Group protocol. Urine samples were collected for cytokine assay at baseline, immediately before and after BCG instillation at 6 wk, and immediately before and after the third BCG instillation of the first maintenance course. Levels of 12 cytokines were measured, and changes from baseline were calculated after treatment. A total of 130 patients were enrolled. Increases in single cytokines correlated with recurrence, but the best predictor of recurrence was changes in a combination of cytokines. A nomogram (CyPRIT) constructed using urinary levels of nine inducible cytokines (IL-2, IL-6, IL-8, IL-18, IL-1ra, TRAIL, IFN-γ, IL-12[p70], and TNF-α) predicted the likelihood of recurrence with 85.5% accuracy (95% confidence interval 77.9–93.1%).” This cytokine panel and nomogram have potential for identifying patients at risk of tumor recurrence during BCG treatment to guide modification of the dose and duration of BCG immunotherapy., Trial Registration: Clinicaltrials.gov NCT01007058., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Periodontal pathogens and/or inflammatory products from periodontitis participate in the development or progression of systemic diseases. In this context, periodontitis acts as a modifying factor to systemic health, including diabetes and cardiovascular diseases. Osteoporosis is an increasingly prevalent condition in our aging population and considered a risk factor for periodontal disease, but the effect of periodontitis on systemic bone homeostasis is unknown. We thus evaluated the effects of experimental periodontitis (EP) on systemic bone loss and the influence of estrogen deficiency in this context, using a mouse model of combined periodontitis and osteoporosis. Experimental periodontitis (EP) was induced by a ligature insertion around the mandibular first molars and Porphyromonas gingivalis infection. Three-dimensional microcomputed tomographic analyses performed 48days following infection revealed that EP and ovariectomy (OVX) induced a significantly higher femoral and mandibular bone loss compared to EP or OVX alone. EP alone did not induce systemic bone loss. In addition, the EP+OVX and EP groups showed significantly higher levels of tumor necrosis factor (TNF)-α than OVX and control groups at end point. These results suggest that periodontitis could be a risk factor for systemic bone loss, especially in post-menopausal women, and warrant further clinical investigations to confirm this association and propose adapted prophylactic and curative therapies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Inflammation is implicated in many adverse health conditions, and recent interest has focused on the effects of chronic low-grade inflammation in generally healthy populations. Cytokines measured in plasma or serum are commonly used as biomarkers of systemic levels of inflammation. Measurement of cytokines in urine may offer a simpler and less invasive alternative, although the degree to which levels of cytokines correlate in plasma and urine among healthy individuals is unknown., Materials and Methods: We assessed the correlation of blood and urine levels of 13 cytokines, including interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12(p70) and IL-13, granulocyte macrophage colony-stimulating factor, interferon gamma and tumour necrosis factor alpha in 61 healthy women aged 18-30. Cytokine concentrations were considered with and without correction for creatinine., Results: Plasma and urine levels of the 13 cytokines were not significantly correlated using measured urinary cytokine concentrations and after adjustment for creatinine. Correlation coefficients for log-transformed cytokine concentrations in paired plasma and urine specimens ranged from -0.28 to 0.087., Conclusions: These results suggest that urine has limited utility as a proxy for plasma for the measurement of inflammatory factors in a healthy population with low levels of inflammation., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

It has been well established that oxidative stress and inflammation are involved in the pathogenesis of diabetic nephropathy. It has been shown that tropisetron exerts anti-inflammatory and immunomodulatory properties. The current study was designed to investigate protective effects of tropisetron on early diabetic nephropathy in streptozotocin-induced diabetic rats. Rats were divided into six groups: (i) untreated diabetic (streptozotocin group); (ii) untreated control; (iii) diabetic rats treated with tropisetron (3 mg/kg); (iv) normal rats treated with tropisetron (3 mg/kg); (v) diabetic rats treated with granisetron (3 mg/kg); and (vi) normal rats treated with granisetron (3 mg/kg); rats began receiving treatment at the time of diabetes induction for 2 weeks. At the termination of the experiments, bodyweight, kidney index, urinary albumin excretion, and glomerular filtration rate were measured. The levels of oxidative stress markers and tumour necrosis factor-α were also determined. Streptozotocin-treated animals showed significant loss of bodyweight and renal enlargement and dysfunction. Diabetic rats also exhibited an increase in malondialdehyde along with a significant decrease in glutathione, superoxide dismutase activity, and catalase activity. Furthermore, the diabetic animals demonstrated a significant rise in renal cortical, urinary tumour necrosis factor-α, and urinary albumin excretion. Both granisetron and tropisetron decreased blood glucose in diabetic animals, but this decrease was not significant for granisetron. Treatment with tropisetron, but not granisetron, prevented increases in oxidative stress and tumour necrosis factor-α, decreased urinary cytokine excretion and albuminuria, and improved renal morphological damage. In conclusion, the present study suggests that tropisetron may be a protective agent in early diabetic nephropathy, and its action is mediated, at least in part, by anti-oxidative and anti-inflammatory mechanisms that appear to be independent of the 5-HT3 receptor., (© 2015 Wiley Publishing Asia Pty Ltd.)

Dimethylarsinic acid (DMA(V) ), the major urinary metabolite of inorganic arsenic, is a urinary bladder carcinogen and bladder tumor promoter in adult rats. Increased urothelial cellular proliferation has been considered as an earlier phenotype in DMA(V) -induced bladder carcinogenesis. The present study examined the ultrastructural changes of bladder epithelial cells and expressions of proliferation factors, as well as the secretion of inflammatory cytokines in rats exposed to DMA(V) for 10 weeks by transmission electron microscopy (TEM), qRT-PCR, immunohistochemical staining and ELISA methods. The results showed that DMA(V) administered in the drinking water produced urothelial cytotoxicity and ultrastructural changes in rats. PCNA, cyclin D1 and COX-2 mRNA expressions and immunoreactivities were elevated in bladder urothelium. In addition, 200 ppm DMA(V) treatment increased the transforming growth factor-beta 1 (TGF-β1) secretion and decreased tumor necrosis factor-alpha (TNF)-α level in the urine of rats. These data suggest that chronic inflammation, bladder epithelium lesions and proliferation might be the basic process of the chronic toxicity effects in DMA(V) -treated rats., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Pathological changes due to infection with Schistosoma haematobium include cytokine-mediated urinary tract inflammation. The involved cytokines may be excreted in urine and their presence in urine may therefore reflect S. haematobium-related urinary tract pathology. The present study, for the first time, reports on the relationship between selected cytokines in urine and infection with S. haematobium in children from an area highly affected by this parasite., Methods: Children aged 5-12 years from two primary schools in Tana Delta District of Kenya were examined for S. haematobium eggs using urine filtration technique, for haematuria using dipstix and for eosinophil cationic protein (ECP), IL-6, IFN- γ, TNF-α and IL-10 levels using ELISA, and for S. haematobium-related urinary tract pathology using ultrasonography. In addition, venous blood was examined for serum IL-6, IFN- γ, TNF-α and IL-10 levels using ELISA., Results: There was no significant correlation between urinary and serum levels of IL-6, IFN- γ, TNF-α or IL-10. There was no significant difference in geometric mean intensity (GMI) in any of the serum cytokines, or in urinary TNF-α or IFN-γ, between children with light and heavy S. haematobium infections. However, children with heavy S. haematobium infections had significantly higher GMI of urinary IL-6 (p < 0.001) and lower GMI of urinary IL-10 (p = 0.002) than children with light infections. There was also a significant positive correlation between urinary IL-6 and urinary ECP (p < 0.001) and a significant negative correlation between urinary IL-10 and urinary ECP (p = 0.012)., Conclusion: Urinary IL-6 was positively correlated to and IL-10 was negatively correlated to infection intensity and urinary tract inflammation in S. haematobium-infected children. Urinary IL-6 and IL-10 ELISA may be a useful non-invasive tool to complement the already available tools for studying S. haematobium-related urinary tract pathology in children.

Novel biomarker discovery plays a crucial role in providing more sensitive and specific disease detection. Unfortunately many low-abundance biomarkers that exist in biological fluids cannot be easily detected with mass spectrometry or immunoassays because they are present in very low concentration, are labile, and are often masked by high-abundance proteins such as albumin or immunoglobulin. Bait containing poly(N-isopropylacrylamide) (NIPAm) based nanoparticles are able to overcome these physiological barriers. In one step they are able to capture, concentrate and preserve biomarkers from body fluids. Low-molecular weight analytes enter the core of the nanoparticle and are captured by different organic chemical dyes, which act as high affinity protein baits. The nanoparticles are able to concentrate the proteins of interest by several orders of magnitude. This concentration factor is sufficient to increase the protein level such that the proteins are within the detection limit of current mass spectrometers, western blotting, and immunoassays. Nanoparticles can be incubated with a plethora of biological fluids and they are able to greatly enrich the concentration of low-molecular weight proteins and peptides while excluding albumin and other high-molecular weight proteins. Our data show that a 10,000 fold amplification in the concentration of a particular analyte can be achieved, enabling mass spectrometry and immunoassays to detect previously undetectable biomarkers.

Objective: We examined the value of inflammatory and oxidative biomarkers in predicting acute kidney injury (AKI) following orthotopic liver transplantation (OLT)., Methods: Urinary excretion of tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), interleukin-10 (IL-10), superoxide dismutase (SOD), malondialdehyde (MDA), 6-keto prostaglandin F1α (6-keto-PGF1α), hydrogen peroxide (H2O2), and 8-keto prostaglandin F2α (8-iso-PGF2α), serum creatinine (SCr), blood urea nitrogen (BUN), urinary N-acetyl-beta-D-glucosaminidase (NAG), β2-microglobulin (β2-MG) and γ-glutamyl-transferase (γ-GT), were measured before surgery (baseline), at 2 h after graft reperfusion and 24 h after OLT in 28 liver transplantation patients., Results: The levels of TNF-α, IL-8, IL-10, SOD, MDA, 6-keto-PGF1α, H2O2 and 8-iso-PGF2α in urine were all significantly higher in patients who had AKI than in those who did not at 2 h after graft reperfusion and 24 h after OLT (p < 0.01).

The study was aimed to investigate the potential mechanism of inflammatory renal damage induced by shock wave. A total of 48 rats, with the right kidney cut, are randomly assigned into control group, ESWL group and ESWL + PDTC group. Rats were treated with shock wave at the left kidney. At post-shock wave 3 and 105 days, all the animals were sacrificed for detecting the expression of tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1, and monocyte chemoattractant protein (MCP)-1. The inflammatory responses were evaluated by detecting the level of myeloperoxidase (MPO) and ED-1. The histological renal injury was also examined. Before the animals were sacrificed, the urine samples were collected for measuring the values of malondialdehyde (MDA), β2-microglobulin, interleukin (IL)-6, and IL-18. At post-shock wave 3 days, the higher expression of ICAM-1 and TNF-α were observed in shock wave-treated kidneys. The level of urine TNF-α, IL-6, and IL-18 were also increased significantly. Using PDTC obviously decreased the expression of ICAM-1 and TNF-α. It also effectively inhibited the degree of oxidative stress and neutrophil infiltration. At post-shock wave 105 days, the expression of MCP-1 and the level of urine β2-microglobulin and IL-18 were increased significantly. The histological analysis also indicated more ED-1-positive cells and serious fibrosis in shock wave-treated kidneys. PDTC significantly suppressed MCP-1 and IL-18 expression, decreased monocyte infiltration, and alleviate the degree of interstitium fibrosis. Shock wave triggered excessive inflammatory responses and aggravated renal biological damage. Several inflammatory factors including ICAM-1, MCP-1, and TNF-α were considered to play important role in this type of renal damage.

The main side effect of cyclosporine A (CsA), a widely used immunosuppressive drug, is nephrotoxicity. Early detection of CsA-induced acute nephrotoxicity is essential for stop or minimize kidney injury, and timely detection of chronic nephrotoxicity is critical for halting the drug and preventing irreversible kidney injury. This study aimed to identify urinary biomarkers for the detection of CsA-induced nephrotoxicity. We allocated salt-depleted rats to receive CsA or vehicle for 7, 14 or 21 days and evaluated renal function and hemodynamics, microalbuminuria, renal macrophage infiltration, tubulointerstitial fibrosis and renal tissue and urinary biomarkers for kidney injury. Kidney injury molecule-1 (KIM-1), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), fibronectin, neutrophil gelatinase-associated lipocalin (NGAL), TGF-β, osteopontin, and podocin were assessed in urine. TNF-α, IL-6, fibronectin, osteopontin, TGF-β, collagen IV, alpha smooth muscle actin (α -SMA) and vimentin were assessed in renal tissue. CsA caused early functional renal dysfunction and microalbuminuria, followed by macrophage infiltration and late tubulointerstitial fibrosis. Urinary TNF-α, KIM-1 and fibronectin increased in the early phase, and urinary TGF-β and osteopontin increased in the late phase of CsA nephrotoxicity. Urinary biomarkers correlated consistently with renal tissue cytokine expression. In conclusion, early increases in urinary KIM-1, TNF-α, and fibronectin and elevated microalbuminuria indicate acute CsA nephrotoxicity. Late increases in urinary osteopontin and TGF-β indicate chronic CsA nephrotoxicity. These urinary kidney injury biomarkers correlated well with the renal tissue expression of injury markers and with the temporal development of CsA nephrotoxicity.

Bladder cancer (BCA) is one of the most common cancers. In 2010 in Poland, 6296 people developed bladder cancer and 3110 people died of it. Immunotherapy with BCG (Bacillus Calmette-Guérin) is by far the most effective adjuvant therapy. Noninfiltrating muscle membrane changes, that is, stages Ta, Tis and T1 qualify for BCG immunotherapy. BCG immunotherapy comprises series of bladder instillations, containing attenuated strain of Mycobacterium bovis. The effectiveness of immunotherapy in non-invasive bladder cancer is 70% 5-year survival without recurrence of the tumor. The treatment leads to a reduction of the residual tumor mass, but also to the delay and/or prevention of relapse, disease progression and ultimately death. Cytokines, as key mediators of immune response, play an important role in the pathogenesis of bladder cancer, which occurrence is stimulated by the inflammatory process. BCG immunotherapy provokes an intensive immunological response by the increase of cytokine production. Genetic variants determine inter-individual differences in the incidence of this cancer, as well as the response to the therapy. This is evidenced by the presence of differences in genetic variants of cytokines correlated with the varied risk of bladder cancer incidence. It is believed that concentrations of particular cytokines in urine after installation of BCG may indicate response to the therapy. Increased levels of Th1 cytokines - IFN-γ, IL-2 and TNF-α are correlated with longer survival time without recurrence, whereas high levels of Th2 cytokines such as IL-10, predict unsuccessful BCG therapy.

Aim: Recent evidence suggests that chronic subclinical inflammation plays a key role in the pathogenesis and progression of diabetic nephropathy. Aim of the present study was to investigate possible correlation between the presence and degree of microalbuminuria and markers of inflammation in patients with type 2 diabetes mellitus (DM)., Patients-Methods: Eighty patients were enrolled and clinical and laboratory data were recorded. Albumin-creatinine ratio (ACR) was calculated in first-morning urine samples. Serum and urinary tumor necrosis factor-α (TNF-α) levels were determined by ELISA., Results: Forty-five patients had normoalbuminuria, 33 microalbuminuria, and 2 macroalbuminuria. Patients with microalbuminuria were older, with higher glycosylated hemoglobin levels (HbA1c) and they more frequently had diabetic retinopathy, neuropathy, and cardiovascular disease and were on treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). ACR was significantly correlated with the presence of cardiovascular disease, hypertension, and HbA1c levels and the administration of clopidogrel and ACEi or ARBs. ACR was not correlated with C-reactive protein, fibrinogen, or serum TNF-α levels but had a strong correlation with urinary TNF-α levels., Conclusions: In patients with type 2 DM, urinary, but not serum, TNF-α levels are associated with the presence and severity of microalbuminuria.

Background/aims: Shiga toxin 2 may trigger classical hemolytic uremic syndrome (HUS) eventually leading to renal failure. Klotho, a transmembrane protein, protease and hormone mainly expressed in kidney is involved in the regulation of renal phosphate excretion and also retains renal protective effects. Renal failure is associated with renal depletion of klotho. The present study explored the influence of Shiga toxin 2 on renal klotho expression., Methods: Mice were injected with either solvent or Shiga toxin 2 and urinary flow rate and phosphate excretion were determined in metabolic cages. Renal transcript levels were measured by quantitative RT-PCR and renal protein abundance by Western blotting. Plasma concentrations of 1,25(OH)2D3 and FGF23 were determined by ELISA and plasma phosphate and urea concentrations by photometry., Results: Shiga toxin 2 treatment was followed by increase of plasma urea concentration, urinary flow rate and renal phosphate excretion but not of plasma phosphate concentration. Shiga toxin 2 treatment strongly decreased klotho mRNA expression and klotho protein abundance in renal tissue. Shiga toxin 2 treatment further increased tumor necrosis factor (Tnfα) mRNA levels, as well as protein abundance of phosphorylated p38 MAPK in renal tissue. The treatment significantly increased renal Cyp27b1 and decreased renal Cyp24a1 mRNA levels without significantly altering plasma 1,25(OH)2D3 levels. Shiga toxin 2 treatment was further followed by increase of plasma FGF23 concentrations., Conclusion: Shiga toxin 2 treatment stimulated Tnfα transcription, down-regulated renal klotho expression and increased FGF23 formation, effects presumably contributing to renal tissue injury., (© 2015 S. Karger AG, Basel.)

Exposure to environmental pollutants has been recognised as a risk factor for cardiovascular events. 1-hydroxypyrene (1-OHP) is a biomarker of exposure to polycyclic aromatic hydrocarbons (PAHs) from traffic-related air pollution. Experimental studies indicate that PAH exposure could be associated with inflammation and atherogenesis. Thus, the purpose of this study was to evaluate whether the biomarker of PAH exposure is associated with biomarkers of inflammation and oxidative stress and if these effects modulate the risk of developing cardiovascular diseases in workers exposed to air pollution. This study included 60 subjects, comprising 39 taxi drivers and 21 non-occupationally exposed persons. Environmental PM2.5 and benzo[a]pyrene (BaP) levels, in addition to biomarkers of exposure and oxidative damage, were determined. Inflammatory cytokines (IL-1β, IL-6, IL-10, TNF-α, IFN-γ and hs-CRP) and serum levels of oxidised LDL (ox-LDL), auto-antibodies (ox-LDL-Ab) and homocysteine (Hcy) were also evaluated. PM2.5 and BaP exhibited averages of 12.4±6.9 μg m(-3) and 1.0±0.6 ng m(-3), respectively. Urinary 1-OHP levels were increased in taxi drivers compared to the non-occupationally exposed subjects (p<0.05) and were positively correlated with pro-inflammatory cytokines and negatively correlated with antioxidants. Furthermore, taxi drivers had elevated pro-inflammatory cytokines, biomarkers of oxidative damage, and ox-LDL, ox-LDL-Ab and Hcy levels, although antioxidant enzymes were decreased compared to the non-occupationally exposed subjects (p<0.05). In summary, our findings indicate that taxi drivers showed major exposure to pollutants, such as PAHs, in relation to non-occupationally exposed subjects. This finding was associated with higher inflammatory biomarkers and Hcy, which represent important predictors for cardiovascular events. These data suggest a contribution of PAHs to cardiovascular diseases upon occupational exposure., (© 2013.)

Background: Long-term renal deterioration is common in patients with posterior urethral valves (PUV), and early identification of detrimental factors can help in counselling patients as well as in guiding future therapy. The aim of our study was (1) to evaluate urinary transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) levels and microalbuminuria before and after ablation of PUV and (2) to examine the effect of early induction of angiotensin-converting enzyme inhibitors (ACE-I) on renal recovery., Methods: The study included 30 patients with diagnosed PUV. Urinary cytokines were measured pre-operatively and post-operatively for 1 year. The study group was subdivided into two subgroups at 6 months after surgery. Group 1 included 16 patients whose urinary TGF-β1 level showed a declining trend. Group 2 included 14 patients whose urinary TGF-β1 showed a rising trend or plateaued; these patients were started on ACE-I therapy, which they received for at least 6 months., Results: Urinary TGF-β1, TNF-α and microalbumin levels were high in patients with PUV. In Group 1 patients, urinary TGF-β1, TNF-α and microalbumin levels fell significantly following valve ablation and continued to decline for 12 months. In Group 2 patients, after an initial fall following valve ablation, urinary TGF-β1, TNF-α and microalbumin showed a continued rise until 6 months post-surgery. After ACE-I therapy, there was 53.43 % fall in urinary TGF-β1, 43.15 % fall in microalbuminuria, 28.57 % improvement in split renal function and 35.80 % improvement in GFR., Conclusions: Based on our results, urinary TGF-β1, urinary TNF-α and microalbuminuria can be used as biomarkers for the early recognition of ongoing renal damage in patients with PUV. ACE-I plays a role in retarding renal damage in these patients.

Aims: The evolution of diabetic nephropathy is incompletely accounted by current clinical tools. New biomarkers may refine patient assessment and help monitor therapy. We compared the added predictive value of 7 candidate inflammatory urinary biomarkers to known risk factors of progression., Methods: We prospectively followed 83 patients with overt diabetic nephropathy for a median 2.1 years and obtained repeated measurements of proteinuria, IL-1β, IL-6, IL-8, MCP-1, TNF-α, TGF-β1, and PAI-1., Results: Patients had an initial estimated glomerular filtration rate of 25 ± 9 mL/min/1.73 m(2), blood pressure of 142/69 mmHg and used a median of 4 anti-hypertensive medications over the course of the study. The observed rate of renal function decline was 2.9 ± 3.0 mL/min/1.73 m(2)/year. All urinary biomarkers levels were collinear and for each one except IL-1β, elevated levels predicted a more rapid progression. MCP-1 was the only biomarker increasing during follow-up, which also correlated with a worst outcome. Using multivariate linear regression adjusting for clinical risk factors of progression, urinary MCP-1 and TGF-β1 predicted progression independently and additively to the degree of proteinuria. We dichotomized these 3 biomarkers and observed a renal function decline with 0, 1, 2 or 3 elevated biomarkers of -0.8 ± 1.4, -2.1 ± 2.1, -4.2 ± 2.8 and -6.0 ± 2.8 mL/min/1.73 m(2)/year, respectively (p<0.001)., Conclusions: Multiple urinary biomarkers predict outcome in overt diabetic nephropathy. However, urinary MCP-1 and TGF-β1 are also independent and additive to proteinuria in predicting the rate of renal function decline and could serve as useful clinical tools in patient risk stratification., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and it is defined as a rise in the urinary albumin excretion (UAE) rate and abnormal renal function. Currently, changes in albuminuria are considered a hallmark of onset or progression of DN. However, some patients with diabetes have advanced renal pathological changes and progressive kidney function decline even if urinary albumin levels are in the normal range, indicating that albuminuria is not the perfect marker for the early detection of DN. The present article provides an overview of the literature reporting some relevant biomarkers that have been found to be associated with DN and that potentially may be used to predict the onset and/or monitor the progression of nephropathy. In particular, biomarkers of renal damage, inflammation, and oxidative stress may be useful tools for detection at an early stage or prediction of DN. Proteomic-based biomarker discovery represents a novel strategy to improve diagnosis, prognosis and treatment of DN; however, proteomics-based approaches are not yet available in most of the clinical chemistry laboratories. The use of a panel with a combination of biomarkers instead of urinary albumin alone seems to be an interesting approach for early detection of DN, including markers of glomerular damage (e.g., albumin), tubular damage (e.g., NAG and KIM-1), inflammation (e.g., TNF-α) and oxidative stress (e.g., 8-OHdG) because these mechanisms contribute to the development and outcomes of this disease., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The prevalence of diabetic nephropathy has tremendously increased with the relentless rise in the incidence of diabetes over the last couple decades. Diabetic nephropathy is a leading cause of morbidity and mortality, and it invariably leads to an end-stage renal disease (ESRD). In an effort to delay the onset of ESRD systematic screening and appropriate management are needed to evaluate the progression of renal damage in diabetic nephropathy. The reliability of current tests in predicting the onset, progression and response to various regimens for diabetic nephropathy is still under debate; and it has engendered a search for more sensitive and specific urinary biomarkers, especially those reflective of tubular dysfunctions. It is well-known that there is a good correlation between the degree of damage to the tubulo-interstitial compartment and the deterioration of renal functions. In view of this, the utility of urinary biomarkers, reflective of tubular injury, reported in the literature is discussed in this brief review.

The study involved 85 patients with chronic pyelonephritis in age from 26 to 62 years. All patients determined C-reactive protein (CRP), interleukin 6 and tumor necrosis factor-alpha in the blood and urine by standard techniques. With the simultaneous study of CRP in the blood and urine of patients with chronic pyelonephritis detected high levels of this biomarker in the urine, which is several times higher than its indicators levels in blood. When studying the levels of proinflammatory cytokines, which are the main inducers excretion of CRP, we found that the increase in their concentration in urine was more pronounced than in the blood, which confirms the opinion that CRP can be synthesized in inflammation focus by lymphocytes, macrophages and endothelial. Studying the levels of cytokines and C-reactive protein in the urine can be used to assess the severity of inflammatory changes in the kidney and to monitor the effectiveness of anti-inflammatory therapy.

Pathways that contribute to TNF production by the kidney are not well defined. Mice given 1% NaCl in the drinking water for 3 days exhibited a 2.5-fold increase in urinary, but not plasma, TNF levels compared with mice given tap water. Since furosemide attenuated the increase in TNF levels, we hypothesized that hypertonic NaCl intake increases renal TNF production by a pathway involving the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). A 2.5-fold increase in NKCC2A mRNA accumulation was observed in medullary thick ascending limb (mTAL) tubules from mice given 1% NaCl; a concomitant 2-fold increase in nuclear factor of activated T cells 5 (NFAT5) mRNA and protein expression was observed in the outer medulla. Urinary TNF levels were reduced in mice given 1% NaCl after an intrarenal injection of a lentivirus construct designed to specifically knockdown NKCC2A (EGFP-N2A-ex4); plasma levels of TNF did not change after injection of EGFP-N2A-ex4. Intrarenal injection of EGFP-N2A-ex4 also inhibited the increase of NFAT5 mRNA abundance in the outer medulla of mice given 1% NaCl. TNF production by primary cultures of mTAL cells increased approximately sixfold in response to an increase in osmolality to 400 mosmol/kgH2O produced with NaCl and was inhibited in cells transiently transfected with a dnNFAT5 construct. Transduction of cells with EGFP-N2A-ex4 also prevented increases in TNF mRNA and protein production in response to high NaCl concentration and reduced transcriptional activity of a NFAT5 promoter construct. Since NKCC2A expression is restricted to the TAL, NKCC2A-dependent activation of NFAT5 is part of a pathway by which the TAL produces TNF in response to hypertonic NaCl intake.

Inflammation is a pathogenic factor for target-organ damage (TOD) in hypertension. This study examined the relationship between inflammatory parameters and urinary albumin excretion (UAE) in prehypertension. A total of 65 prehypertensive subjects (blood pressure (BP) 120-139/80-89 mm Hg) and 26 healthy volunteers with BP <120/80 mm Hg were included. High-sensitivity C-reactive protein (hs-CRP), and serum and urinary tumor necrosis factor-α (TNF-α) were measured as inflammatory markers. Prehypertensive individuals had higher levels of inflammatory parameters and UAE than healthy subjects. Analyses carried out in prehypertensive participants showed that BP was similar between individuals with normoalbuminuria or microalbuminuria (MAB) (UAE between 30 and 299 mg per day). However, serum hs-CRP and urinary TNF-α excretion were higher in prehypertensives with MAB. Multiple regression analysis showed that systolic blood pressure (r=0.29, P<0.01), hs-CRP (r=0.20, P<0.001), and urinary TNF-α (r=0.69, P<0.001) were independently correlated with UAE (adjusted R(2)=0.73, P<0.001). Finally, logistic regression analysis performed in the prehypertensive group with the absence or presence of MAB as the dependent variable demonstrated that hs-CRP (3.92 (1.45-10.58), P=0.007) and urinary TNF-α (1.69 (1.20-2.37), P=0.002) were independent risk factors for the presence of MAB. Inflammatory parameters are significantly and independently associated with UAE in prehypertensive subjects, suggesting that inflammation may be a pathogenic factor for the early vascular or TOD in these individuals.

We studied asymptomatic primary schoolchildren in northeastern Malaysia with light to moderate trichuriasis to determine the effect of albendazole treatment on growth rates and TNF-alpha levels. Thirty-seven schoolchildren aged 6-7 years with stool samples positive for Trichuris trichiura and negative for other geohelminths and protozoa were randomized to receive albendazole 400 mg or a placebo daily for 2 days. Anthropometric parameters at baseline, 3, 6 and 12 months were compared between the 2 groups. The placebo group had a significantly greater increase in height (p = 0.04) than the albendazole treatment group. There were no significant differences in urinary TNF-alpha levels (p = 0.8) between the 2 groups and no significant changes between baseline and 1 month post-treatment levels. Further studies are needed to determine the etiology of this apparent association between the albendazole treatment group and the delay in growth rate at 6 months post-treatment.

Objective: The aim of this study was to explore the role of cytokines in the pathogenesis of hemorrhagic fever with renal syndrome (HFRS)., Methods: Double-antibody sandwich ELISA was used to determine serum interleukin (IL)-6, urine tumor necrosis factor (TNF), IL-6, and IL-8 levels in 56 patients with HFRS., Results: Serum IL-6, urine TNF, IL-6, and IL-8 concentrations in HFRS patients were significantly higher than those in the control group (p<0.001). The concentrations increased at fever stage, then continued to increase during the hypotension stage and peaked at the oliguria stage. The concentrations of serum IL-6, urine TNF, IL-6, and IL-8 increased according to the severity of the disease, and differed greatly among different types of the disease. Serum IL-6 had remarkable relationships with serum specific antibodies. It was positively related to serum β2-microglobulin (β2-MG), blood urea nitrogen (BUN), and creatinine (Cr). Significant positive relationships were also found both between urine IL-6 and TNF, and between IL-6 and IL-8 (r=0.5768, p<0.05; r=0.3760, p<0.01)., Conclusion: TNF, IL-6, and IL-8 were activated during the course of the disease. IL-6 was associated with the immunopathological lesions caused by the hyperfunction of the humoral immune response. IL-6, IL-8 and TNF were involved in renal immune impairment. Determining them might, to a certain extent, be useful in predicting the prognosis and outcome of patients with HFRS., (Copyright © 2012 Elsevier Editora Ltda. All rights reserved.)

The effect of tumor necrosis factor-alpha (TNF) on cyclooxygenase-2 (COX-2) expression in the renal outer medulla (OM) was determined in a model of dihydrotachysterol (DHT)-induced hypercalcemia. Increases in serum calcium and water intake were observed during ingestion of a DHT-containing diet in both wild type (WT) and TNF deficient mice (TNF(-/-)). Polyuria and a decrease in body weight were observed in response to DHT treatment in WT and TNF(-/-) mice. A transient elevation in urinary TNF was observed in WT mice treated with DHT. Moreover, increased urinary levels of prostaglandin E(2) (PGE(2)) and a corresponding increase in COX-2 expression in the OM were observed in WT mice fed DHT. Increased COX-2 expression was not observed in TNF(-/-) mice fed DHT, and the characteristics of PGE(2) synthesis were distinct from those in WT mice. This study demonstrates that COX-2 expression in the OM, secondary to hypercalemia, is TNF-dependent., (Copyright © 2012 Elsevier Inc. All rights reserved.)