Urinary N-acetyl-β-D-glucosaminidase Research Articles

Association between chronic lead exposure and markers of kidney injury: A systematic review and meta-analysis.

In view of inconsistent reports on the association between chronic lead (Pb) exposure and renal injury markers (potential site of injury), the present systematic review explored their association by reviewing studies that investigated chronic Pb-exposed and those without obvious Pb exposure.Studies reporting blood Pb levels(BLL) and biomarkers of kidney injury [i.e. N-acetyl-β-D-glucosaminidase (NAG), Micro-Globulin(μG) and others] among chronic Pb-exposed and unexposed individuals were systematically searched from digital databases available until February 26, 2024. Preferred Reporting Items of Systematic Reviews and Meta-Analysis Guidelines were adhered to during the execution. Pooled effect size and heterogeneity were estimated using the random effect model and I2 index. The risk of biases & certainty of evidence among the included studies was assessed using the Newcastle Ottawa Scale & GRADE, respectively. Sub-group, sensitivity and meta-regression analyses were performed when data permitted.Pooled quantitative analysis revealed elevated BLL [25.64 (21.59-29.70) µg/dL] Pb-exposed group. The pooled analysis confirmed significantly higher urinary NAG [0.68(0.26-1.10) units], α1μG [3.82(0.96-6.68) mg/g creatinine] β2μG [1.5(0.86-2.14) units and serum creatinine [0.03(0.00-0.05) mg/dL] levels in Pb-exposed group, with high heterogeneity.Current observations indicate the proximal tubular injury as the early and potential site of Pb-induced renal injury. Pb-exposed individuals experience proximal tubular injury (KIM-1, NAG) and dysfunction (β2μG, α1μG, Cystatin-C) prior to obvious clinical renal failure. Present observations should caution the policymakers towards drafting regulations for periodic screening with markers of renal injury and / or dysfunction among those chronically exposed to lead despite the certainty of evidence is very low.

Changes in urinary renal injury markers in children with Mycoplasma pneumoniae pneumonia and a prediction model for related early renal injury

BackgroundThis study aims to analyse changes in urinary kidney injury markers in children with Mycoplasma pneumoniae pneumonia (MPP), investigate the risk factors for MPP-related acute kidney injury (AKI) and establish a model to predict MPP-related AKI.MethodsNinety-five children were enrolled based on the study’s inclusion and exclusion criteria. They were divided into a severe MPP (SMPP) group and a non-SMPP group and then into an AKI group and a non-AKI group according to the presence of AKI. A univariate logistic regression analysis was performed to explore the early risk factors for AKI. Based on a multivariate logistic regression analysis and a least absolute shrinkage and selection operator regression analysis, appropriate variables were selected to establish a prediction model, and R 4.2.2 software was used to draw nomograms and generate a dynamic nomogram website.ResultsSeven urinary kidney injury markers were abnormally elevated in the SMPP group and the non-SMPP group: urinary N-acetyl-β-D-glucosaminidase (NAG), β2-microglobulin, α1-microglobulin, retinol-binding protein, urinary immunoglobulin G, urinary transferrin and urinary microalbumin. Sixteen children were identified with AKI during hospitalisation. The AKI group had higher levels of urinary NAG, α1-microglobulin, β2-microglobulin, urinary microalbumin, urinary transferrin and retinol-binding protein than the non-AKI group (P < 0.05). The MPP-related AKI prediction model consists of four indicators (serum immunoglobulin M [IgM], C-reactive protein [CRP], urine NAG and sputum plug presence) and a dynamic nomogram.ConclusionUrinary kidney injury markers are often elevated in children with MPP; urinary NAG is the marker most likely to be elevated, and it is especially evident in severe cases. The nomogram of the prediction model, comprising serum IgM, CRP, urinary NAG and sputum plug presence, can predict the probability of AKI in children with MPP.

Urinary N-acetyl-D-glucosaminidase can predict bleeding after a percutaneous kidney biopsy

BackgroundA percutaneous kidney biopsy (PKB) allows nephrologists to make informed decisions for treating various kidney diseases; however, the risk of bleeding complications should be considered, given the vascularity of the kidney. Many studies have reported risk factors for bleeding events after a PKB. However, while urinary N-acetyl-β-D-glucosaminidase (NAG) is a useful biomarker of kidney disease severity, little is known about whether or not urinary NAG is related to the bleeding risk.MethodsMedical records of patients who underwent a PKB at the National Defense Medical College Hospital between October 2018 and October 2023 were retrospectively studied. Hemoglobin (Hb) loss ≥ 1 g/dL was defined as a bleeding event.ResultsOf the 213 patients, 110 (51.6%) were men, and the median age was 56 years old (interquartile range 40–71). The most frequent diagnosis on a PKB was IgA nephropathy (N = 72; 34.0%). Fifty-four patients (25.3%) experienced Hb loss ≥ 1 g/dL after a PKB, and urinary NAG/Cr levels before the biopsy were able to predict a bleeding event, with an area under the receiver operating characteristic curve of 0.65 (p = 0.005). Using the optimal cutoff value of 35 U/gCr, urinary NAG/Cr was found to be an independent risk factor by multiple logistic regression analysis (odds ratio 3.21, 95% confidence interval 1.42–7.27, p = 0.005). Even after adjusting for previously-reported risk factors, the elevated urinary NAG/Cr ratio remained a statistically significant variable. Compared with the pathological findings, only the severity of multilayered elastic laminae of the small muscular artery was associated with both urinary NAG/Cr levels (p = 0.008) and bleeding events (p = 0.03).ConclusionUrinary NAG successfully predicted not only the severity of kidney disorders but also bleeding events after a PKB. Arteriosclerosis in the kidneys may be the mechanism underlying these increased bleeding events.

Estimation of urinary cadmium benchmark dose thresholds for preschool children in a cadmium-polluted area based on Bayesian model averaging.

Urinary cadmium (U-Cd) values are indicators for determining chronic cadmium toxicity, and previous studies have calculated U-Cd indicators using renal injury biomarkers. However, most of these studies have been conducted in adult populations, and there is a lack of research on U-Cd thresholds in preschool children. We aimed to apply benchmark dose (BMD) analysis to estimate the U-Cd threshold level associated with renal impairment in preschool children in the cadmium-polluted area. 518 preschool children aged 3-5years were selected by systematic sampling (275 boys, 243 girls). Urinary cadmium and three biomarkers of early renal injury (urinary N-acetyl-β-D-glucosaminidase, UNAG; urinary β2-microglobulin, Uβ2-MG; urinary retinol-binding protein, URBP) were determined. Bayesian model averaging estimated the BMD and lower confidence interval limit (BMDL) of U-Cd. The medians U-Cd levels in both boys and girls exceeded the recommended national standard threshold (5μg/gcr) and U-Cd levels were higher in girls than in boys. Urinary N-acetyl-β-D-glucosaminidase (UNAG) was the most sensitive biomarker of renal effects in preschool children. The overall BMDL5 (BMDL at a benchmark response value of 5) was 2.76μg/gcr. In the gender analysis, the BMDL5 values were 1.92μg/gcr for boys and 4.12μg/gcr for girls. This study shows that the U-Cd threshold (BMDL5) is lower than the national standard (5μg/gcr) and boys' BMDL5 was lower than the limit set by the European Parliament and Council in 2019 (2μg/gcr), which provides a reference point for making U-Cd thresholds for preschool children.

Tachycardia and Acute Kidney Injury among Critically Ill Patients with Sepsis: A Prospective Observational Study

Introduction: Tachycardia caused by sympathetic overactivity impairs myocardial function and raises septic patients’ mortality. This study examined whether tachycardia is associated with acute kidney injury (AKI) period-prevalence among critically ill patients with and without sepsis. Methods: In 328 patients (119 sepsis and 209 non-sepsis) admitted to our intensive care unit (ICU), we assessed heart rate at ICU admission, plasma neutrophil gelatinase-associated lipocalin (NGAL) and N-terminal pro-B-type natriuretic peptide, and urinary L-type fatty acid-binding protein and N-acetyl-β-d-glucosaminidase (NAG) at 0 and 48 h after admission. Tachycardia was defined as a heart rate above 100 beats/min. Results: Tachycardia was independently correlated with AKI prevalence during the first week after ICU admission in the septic patients, but not in the non-septic patients. A dose-dependent increase in AKI period-prevalence was observed across ascending heart rate ranges. Furthermore, we discovered a dose-dependent increase in renal biomarker-positive patients regarding plasma NGAL and urinary NAG over increasing heart rate ranges 48 h after admission. Conclusion: The findings revealed an independent relationship between tachycardia and AKI prevalence during the first week of ICU in septic patients. Heart rate was found to have a dose-dependent effect on AKI prevalence and renal insult monitored by biomarkers.

UNC93B1 Mediates the Effects of cGAS-STING on ER Stress and Iron Death, and Reduces Renal Toxicity in Cadmium-Exposed Rats.

Long-term exposure to cadmium can induce renal toxicity in rats, leading to endoplasmic reticulum (ER) stress and iron death. Notably, in cadmium-exposed rats, there is an increased expression of UNC93B1 (unc-93 homolog B1). Consequently, our investigation aims to determine the impact of UNC93B1 on ER stress and iron death in cadmium-exposed rats by modulating the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway. A cadmium-exposed rat model was established by intrabacally injecting chromium chloride (5 mg/kg, once a day for 4 weeks), and the levels of UCd (urine cadmium), UNAG (urine N-acetyl-β-D-glucosaminidase), and UCr (urine creatinine) in urine were assessed. A silent UNC93B1 lentivirus was constructed, and STING agonists were procured and administered to the rats. Subsequently, kidney tissues were extracted post-mortem, and pathological changes in renal tissue were observed through hematoxylin and eosin (HE) staining. The expression and mRNA levels of UNC93B1, cGAS, and STING were examined using western blot (WB) and polymerase chain reaction (PCR). Autophagy proteins (light chain 3 (LC3), Beclin-1, p62) were also assessed by WB. Additionally, iron concentration was determined using a kit, while oxidative stress markers (cytochrome oxidase subunit 2 (COX2), glutathione peroxidase 4 (GPX4), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH)) were measured through enzyme-linked immunosorbent assay (ELISA). Furthermore, endoplasmic reticulum stress proteins (protein kinase RNA-like ER kinase (PERK), CCAAT enhance-binding protein homologous protein (CHOP), activating transcription factor-4 (ATF4)) were analyzed by WB. Wstaining, WB, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), ELISA, and HE staining collectively revealed a heightened expression of UNC93B1, cGAS, and STING, accompanied by increased levels of autophagy, oxidative stress, and ER stress in cadmium-exposed rats (p < 0.05). Nephrotoxicity exhibited a reduction following the inhibition of UNC93B1, leading to decreased levels of oxidative stress, autophagy, and ER stress (p < 0.05). Notably, this observed phenomenon was reversed upon the addition of STING agonists, suggesting that UNC93B1 might exert a nephroprotective effect in cadmium-exposed rats through modulation of the cGAS-STING pathway. The inhibition of UNC93B1 mitigates nephrotoxicity in cadmium-exposed rats, and this protective effect is mechanistically linked to the cGAS-STING pathway.

Impact of multi-heavy metal exposure on renal damage indicators in Korea: An analysis using Bayesian Kernel Machine Regression.

Exposure to cadmium (Cd), arsenic (As), and mercury (Hg) is associated with renal tubular damage. People living near refineries are often exposed to multiple heavy metals at high concentrations. This cross-sectional study investigated the association between combined urinary Cd, As, and Hg levels and renal damage markers in 871 residents living near the Janghang refinery plant and in a control area. Urinary Cd, As, Hg, N-acetyl-β-D-glucosaminidase (NAG), and β2-microglobulin (β2-MG) levels were measured. The combined effects of Cd, As, and Hg on renal tubular damage markers were assessed using linear regression and a Bayesian Kernel Machine Regression (BKMR) model. The results of the BKMR model were compared using a stratified analysis of the exposure and control groups. While the linear regression showed that only Cd concentration was significantly associated with urinary NAG levels (β = 0.447, P value < .05), the BKMR model showed that Cd and Hg levels were also significantly associated with urinary NAG levels. The combined effect of the 3 heavy metals on urinary NAG levels was significant and stronger in the exposure group than in the control group. However, no relationship was observed between the exposure concentrations of the 3 heavy metals and urinary β2-MG levels. The results suggest that the BKMR model can be used to assess the health effects of heavy-metal exposure on vulnerable residents.

#5402 ASSOCIATION BETWEEN URINARY N-ACETYL-β-D-GLUCOSAMINIDASE AND BISPHENOL AND ITS SUBSTITUTE EXPOSURE IN TAIWANESE ADULTS

Abstract Background and Aims Urinary N-acetyl-β-D-glucosaminidase (NAG) is a sensitive and reliable indicator of renal damage, like proximal tubular cell injury. Bisphenol A (BPA), a known endocrine disruptor, or its substitute has been reported as a risk factor that caused kidney damage in experimental studies. We aimed to investigate the correlation between urinary NAG and Bisphenol and its Substitute Exposure in Taiwanese Adults. Method We collected urine samples including 271 adults (145 female and 126 men) from Taiwan Environmental Survey for Toxicants 2013, and analyzed for three urinary BPA, BPS and BPF by using ultraperformance liquid chromatography–tandem mass spectrometry. The bisphenol and their substitutes in the human urine samples were converted into daily intake (DI) values. We measured by the indicators of renal function, included urine creatinine (crea, mg/dL), microalbumin (mg/dL), NAG (IU/L), etc. We used logistic regression analysis to elucidate their correlations and adjustment for significant covariate. Results We found the median levels were 7.96 for BPA, 7.89 for BPF, and 1.96 (μg/L) for BPS, respectively, and yielded a median estimate daily intakes were 3.01 (BPA), 2.99 (BPF), and 0.76 (BPS) (ng/kg/day) in the Taiwanese adults. We found that the ratio of urinary NAG and creatinine (NAG/crea) was a significantly increased trend with exposure doses of BPA, BPF and BPS whereas no similar trend for ACR. After adjustment for age, sex, BMI and other covariate, we found that DI of BPA increased the risk of NAG/crea by 5.8 times (ORAdj: 5.8, p&amp;lt;0.01, 2nd tertile) and 9.6 times (ORAdj: 9.6, p&amp;lt;0.01, 3rd tertile). Conclusion Our findings supported that the exposure of bisphenol and its substitute may increase the risk of renal tubular injury. Further large and longitudinal studies are warrant.

Increased urinary albumin leakage is related to injuries of glomerular glycocalyx and podocytes, and associated with tubular dysfunction in preeclampsia.

The pathogenesis of preeclampsia (PE) is known to be endothelial cell damage; however, the existence of dysfunction in glomerular endothelial glycocalyx, podocytes and tubules remains unclear. The glomerular endothelial glycocalyx, basement membrane, podocytes, and tubules are permeability barriers against albumin excretion. This study aimed to assess the relationship between urinary albumin leakage and injuries of the glomerular endothelial glycocalyx, podocytes, and tubules in patients with PE. A total of 81 women with uncomplicated pregnancies (control, n=22), PE (PE, n=36), or gestational hypertension (GH) (GH, n=23) were enrolled. We assessed urinary albumin and serum hyaluronan for glycocalyx injuries, podocalyxin for podocytes injuries, and urinary N-acetyl-β-d-glucosaminidase (NAG) and liver-type fatty acid-binding protein (l-FABP) for renal tubular dysfunctions. The serum hyaluronan and the urinary podocalyxin levels were higher in the PE and GH groups. The urinary NAG and l-FABP levels were higher in the PE group. Urinary NAG and l-FABP levels positively correlated with urinary albumin excretion. Our findings suggest that increased urinary albumin leakage is related to injuries of the glycocalyx and podocytes, and associated with tubular dysfunction in pregnant women with PE. The clinical trial described in this paper was registered at the UMIN Clinical Trials Registry under registration number UMIN000047875. URL of registration: https://centre6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000054437.

The Association Between Environmental Cadmium Exposure and Parathyroid Hormone Levels.

Cadmium exposure is associated with renal dysfunction and bone damage. Chronic kidney disease and bone loss are also related to parathyroid hormone (PTH). However, whether cadmium exposure affect PTH level is not completely understood. In this study, we observed the association between environmental cadmium exposure and PTH levels in a Chinese population. A ChinaCd study was performed in China in 1990s which included 790 subjects living in heavily, moderately and low cadmium polluted area. 354 of them (121 men and 233 women) also had the data of serum PTH. The cadmium levels in blood (BCd) and urine (UCd) were determined by flame atomic absorption spectrometry. Serum PTH was detected by immunoradiometric assay. Renal function was assessed based on urinary N-acetyl-β-d-glucosaminidase (UNAG), β2-microglobulin (UBMG) and urinary albumin (UALB). The median BCd and UCd levels were 4.69 μg/L and 5.50 μg/g creatinine. The BCd, UCd, UNAG, UBMG and UALB levels in subjects with low PTH (< 5.0 ng/L) were significantly higher than those with PTH ≥ 5.0 ng/L (p < 0.05 or p < 0.01). Spearman correlation analysis also showed that UCd level was negatively correlated to PTH levels (r = -0.17, p = 0.008)in women. A weak correlation was also observed between PTH level and BCd in women (r = -0.11, p = 0.09) and UBMG in total population(r = -0.114, p = 0.07). Univariable and mutivariable logistic regression analysis both demonstrated that high BCd (> 10 μg/L) (odds ratio (OR) = 2.26, 95% confidence interval (CI):1.10-4.63; OR = 2.36, 95%CI: 1.11-5.05) and UCd level (> 20 μg/g cr) (OR = 2.84, 95% CI:1.32-6.10; OR = 2.97, 95%CI: 1.25-7.05) were associated with high risk of low PTH. Our data showed that environmental cadmium exposure was associated with low PTH level.

Continuous positive airway pressure treatment reduces renal tubular damage in patients with obstructive sleep apnea: A retrospective single-center cohort study

BackgroundChronic intermittent hypoxia (IH) plays a significant role in the pathogenesis of obstructive sleep apnea (OSA) comorbidities. The prevalence of chronic kidney disease is higher in patients with OSA than the general population, and renal function decline is well correlated with renal tubular injury. However, little is known about the impact of OSA-induced chronic IH on the renal tubules. MethodsWe conducted a retrospective survey of clinical records performing multiple regression analysis and cluster analysis with particular attention to the 3% oxygen desaturation index (ODI) and urinary N-acetyl-β-d-glucosaminidase (NAG). ResultsIn patients with suspicion of OSA, urinary NAG creatinine ratio (UNCR) was elevated as their 3% ODI increased (n = 197, p < 0.001), and the elevated UNCR decreased following CPAP treatment in patients with OSA (n = 46, p = 0.014). Multiple regression analysis showed that 3% ODI was associated with UNCR. Cluster analysis identified three clusters of patients with OSA, including two younger age clusters, one of which was characterized by high BMI, high 3% ODI, and high prevalence of major comorbidities. In a comparative analysis of younger age cases (age ≤ 55, n = 82), the UNCR level was higher in patients with severe 3% ODI (3% ODI > 40 events/h, n = 24) (p = 0.014). ConclusionsOur results indicate that even at younger ages, OSA patients with severe chronic IH and major comorbidities are susceptible to renal tubular damage. Early treatment with CPAP may attenuate renal tubular injury and progression toward end-stage renal disease.

Cadmium body burden and health effects after restoration of cadmium-polluted soils in cadmium-polluted areas in the Jinzu River basin.

Itai-itai disease is caused by environmental cadmium (Cd) pollution in the Jinzu River basin in Japan. To reduce the Cd contamination of rice, soil restoration of paddy fields was carried out. We evaluated the effect of soil restoration on the health status of residents of the former Cd-polluted area. Participants were 1,030 men and 944 women who lived in the area of restoration of Cd-polluted rice paddies. First morning urine was collected and urinary Cd, β2-microglobulin (β2MG), and N-acetyl-β-D-glucosaminidase (NAG) levels were measured. Associations among age, years of residence before and after soil restoration, and urinary Cd, β2MG, and NAG levels were evaluated by multiple regression analysis. The geometric mean (interquartile range) of urinary Cd (µg/g Cr) was 1.00 (0.58-1.68) in men and 1.67 (1.02-2.91) in women. The geometric means of urinary β2MG (µg/g Cr) and NAG (U/g Cr) were 174.6 (92.6-234.2) and 1.47 (0.72-3.14) in men, and 217.6 (115.3-28.7) and 1.48 (0.73-2.96) in women, respectively. Urinary Cd, β2MG, and NAG were significantly positively correlated (p < 0.01 all). Age and duration of residence in the Cd-polluted area before soil restoration were independently associated with urinary Cd, β2MG, and NAG. Among the 916 participants who had resided in the area before the soil restoration, urinary Cd concentrations were significantly higher, thus by 1.03-fold (95% CI, 1.01-1.04) in men and 1.03-fold (95% CI, 1.01-1.05) in women, when the years of residence before soil restoration by each 5-years increment. By contrast, urinary Cd concentrations were significantly lower, thus 0.97-fold (95% CI, 0.96-0.99) lower in men and 0.97-fold (95% CI, 0.95-0.99) lower in women, by each 5-year increment of residence after soil restoration. A similar association was observed for urinary β2MG concentration, and no significant association was observed for urinary NAG levels in men or women. Cd exposure and associated renal tubular dysfunction in residents of a former Cd-polluted area were influenced by Cd exposure from the environment prior to soil restoration. Soil restoration in Cd-polluted areas reduced the Cd exposure of local residents.

Urinary RBP as an Independent Predictor of Renal Outcome in Diabetic Nephropathy.

Background Renal tubular impairment is prevalent in diabetic nephropathy (DN) and the histological severity predicted renal outcome. Biomarkers of tubular injury also increased in the urine of DN patients. The retrospective study aimed to assess the prognostic value of clinically widely applied urinary tubular injury markers, retinol-binding protein (RBP), β2-microglobulin (β2-MG) and N-acetyl-β-D-glucosaminidase (NAG) in DN. Method A total of 305 patients with biopsy-proven DN were enrolled. The baseline urine total protein and components including albumin, IgG, RBP, β2-MG and NAG were retrieved from medical records. The primary outcome was end stage renal disease (ESRD). Cox proportional hazard analysis and restricted cubic splines were performed to evaluate the association of parameters with ESRD. Nomograms were constructed and concordance index (C-index) was used to measure the prediction ability. Result The levels of urinary RBP, β2-MG and NAG were positively correlated with the severity of interstitial fibrosis and tubular atrophy (IFTA). Positive correlations were also observed among β2-MG, NAG and mesangial expansion. Urinary RBP was not correlated with any glomerular lesions. Urinary RBP, β2-MG and NAG were risk factors for ESRD in hazard analysis with adjustment for age, gender and body mass index (BMI). The hazard ratios increased with the increment of baseline levels. In the multivariate Cox model including serum creatinine (SCr), total urinary protein, urinary albumin, urinary IgG and the tubular injury biomarkers, urinary RBP (with every g/mol.Cr increase: HR 1.06, 95% CI 1.03-1.10, p =0.001) remained as an independent risk factor for ESRD in DN patients. Patients were divided by the medium value of urinary RBP into the low RBP and high RBP groups. Survival analysis showed that significantly more patients in the high RBP progressed to ESRD compared to those in the low RBP group (p =0.02) when urinary total protein was less than 3.5 g/g. The C-index of the nomogram incorporating age, gender, BMI, SCr and total urine protein was 0.757. The value increased to 0.777 after adding urinary RBP to the model. Conclusions Urinary RBP excretion was only correlated with the severity of IFTA and independently predicted ESRD in DN patients.

Associations of urinary orosomucoid, N-acetyl-β-D-glucosaminidase, and albumin with blood pressure and hypertension after 7 years. The Tromsø Study

Purpose: Subclinical chronic kidney disease is known to exacerbate hypertension and progression of kidney damage. In order to initiate timely interventions, early biomarkers for this vicious circle are needed. Our aim was to describe the cross-sectional associations of urinary orosomucoid and urinary N-acetyl-β-D-glucosaminidase (NAG) with blood pressure and the longitudinal associations of urinary orosomucoid and NAG to hypertension after 7 years, and to compare the strength of these associations to the urinary albumin excretion (UAE). Material and methods: The Tromsø Study is a population-based, prospective study of inhabitants of the municipality of Tromsø, Northern Norway. Morning spot urine samples were collected on three consecutive days in the Tromsø 6 survey (2007–2008). We assessed the cross-sectional associations of urinary orosomucoid, NAG and UAE with blood pressure in Tromsø 6. In a cohort of participants attending Tromsø 6 and Tromsø 7 (2015–2016), we studied whether urinary biomarkers were longitudinally associated with hypertension. Results: A total of 7197 participants with a mean age of 63.5 years (SD 9.2), and a mean blood pressure of 141/78 mmHg (SD 23.0/10.6), were included in the study. Orosomucoid and UAE, but not NAG, was significantly associated with systolic and diastolic blood pressure in all the crude and multivariable cross-sectional analyses. Orosomucoid had consistently, although marginally, stronger associations with blood pressure. Incident hypertension at follow-up (Tromsø 7) was consistently significantly associated with urinary orosomucoid, but not urinary NAG or UAE. However, the standardized regression coefficients for orosomucoid were only marginally stronger than the standardized regression coefficients for ACR. Conclusion: In a cohort from the general population urine orosomucoid had a stronger cross-sectional association with blood pressure than UAE. After 7 years, urine orosomucoid showed the strongest association with incident hypertension. There were varying and weak associations between U-NAG, blood pressure and hypertension.

Efficacy and safety of tailin formulation combined with continuous low-dose antibiotic therapy in patients with recurrent urinary tract infection: A multicenter, randomized, controlled clinical trial

Persistent inflammation associated with recurrent urinary tract infection (rUTI) is a crucial inducement of inflammation-driven renal fibrosis (IDRF). Although continuous low-dose antibiotic therapy (CLAT) is the common treatment for rUTI, its clinical efficacy remains unsatisfactory. Tailin formulation (TLF), a Chinese herbal formulation prescribed for treating rUTI, is effective in alleviating symptoms and reducing recurrence. This study was to evaluate the efficacy and safety of TLF combined with CLAT compared with CLAT used alone in patients with rUTI. In this multicenter, randomized, controlled clinical trial, patients were assigned (1:1) to receive either TLF + CLAT or CLAT for 12 weeks. The primary outcome was the effective rate at week 12 of the treatment. The secondary outcomes were the recurrent rate at week 4 and week 12 post treatment; the post-treatment changes in renal tubular injury markers (urinary N-acetyl-β-d-glucosaminidase (NAG) and β2-microglobulin (β2-MG)), profibrotic factors (urinary monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor beta1 (TGF-β1)), and traditional Chinese medicine (TCM) symptoms, and vital signs indicators and serious adverse events (SAEs) were also monitored throughout the trial. A total of 195 patients were included in the final analysis. The TLF + CLAT group had a higher effective rate and a lower recurrence rate than the CLAT group (p < 0.01). Significant decrease of urinary NAG and β2-MG was observed in the TLF + CLAT group vs. CLAT group (p < 0.01), and similar changes were observed in profibrotic factors (urinary MCP-1 and TGF-β1) (p < 0.05), which indicated that TLF might have potential renal tubular protection and anti-fibrosis effects. Additionally, a positive correlation within a certain range was shown in the correlation analysis of medical history (months) of rUTI patients with urinary MCP-1 (r = 0.50, p < 0.05) and TGF-β1 (r = 0.78, p < 0.01). A significant difference was also observed in TCM symptoms (p < 0.01). There were no obvious adverse reactions that occurred during this study. We conclude that TLF combined with CLAT was superior to CLAT used alone in reducing rUTI recurrence, alleviating the non-infection-related physical symptoms and protecting renal tubular and anti-fibrosis, which suggests this novel therapy might be an available treatment with great promise in treating rUTI.

High Glycated Hemoglobin Instead of High Body Mass Index Might Increase the Urine N-Acetyl-β-D-glucosaminidase Con-Centration in Children and Adolescents with Diabetes Mellitus.

Children with diabetes, and particularly those with obesity, have poor glycemic control. They are thus at higher risk of early microvascular complications. Renal tubulointerstitial markers are integral to evaluating diabetic nephropathy. Various biomarkers have been proposed, but their role in the obese pediatric population is uncertain. We investigated renal injury markers in children with diabetes, according to obesity, and determined their role as early predictors of diabetic nephropathy. Fifty-three children and adolescents, diagnosed with either type 1 or 2 diabetes mellitus, and 43 control children, aged 7–18 years, were included. Clinical and laboratory characteristics, including six renal injury markers, were compared among subjects according to body mass index and presence of diabetes mellitus. Urine neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and N-acetyl-β-D-glucosaminidase (NAG) showed significant difference between controls and diabetic children, whereas urine NAG was the only biomarker that was significantly lower either in non-obese or obese controls as compared to diabetic children. Urine NGAL, KIM-1, and NAG showed significant correlations with both HbA1c and urine ACR, whereas only urine NAG was significantly correlated with HbA1c even when groups were subdivided based on the presence of either obesity or diabetes. After adjusting for age, sex, body mass index, duration of known diabetes, and urine albumin-to-creatinine ratio, HbA1c remained a significant risk factor for elevated urine NAG. Urine NAG could be a useful indicator of tubulointerstitial damage in children with diabetes in the pre-albuminuric state. Tighter glycemic control appears to be crucial for avoiding early progression to diabetic nephropathy.

Urinary cadmium and peripheral blood telomere length predict the risk of renal function impairment: a study of 547 community residents of Shanxi, China.

Few reports have investigated the predictive value of urinary cadmium (UCd) and telomere length on renal function impairment. Therefore, we constructed nomogram models, using a cross-sectional survey to analyze the potential function of UCd and telomere length in renal function impairment risk. We randomly selected two community populations in Shanxi, China, and general information of the subjects was collected through face-to-face questionnaire surveys. Venous blood of subjects was collected to detect absolute telomere length (ATL) by real-time quantitative chain reaction (RT-PCR). Collecting urinary samples detected UCd and urinary N-acetyl-β-d-glucosaminidase (UNAG). Estimated glomerular filtration rate (eGFR) was obtained based on serum creatinine (SCr). Nomogram models on risk prediction analysis of renal function impairment was constructed. After adjusting for other confounding factors, UCd (β = 0.853, 95% confidence interval (CI): 0.739 ~ 0.986) and ATL (β = 1.803, 95%CI: 1.017 ~ 1.154) were independent risk influencing factors for increased UNAG levels, and the risk factors for eGFR reduction were UCd (β = 1.011, 95%CI: 1.187 ~ 1.471), age (β = 1.630, 95%CI: 1.303 ~ 2.038), and sex (β = 0.181, 95%CI: 0.105 ~ 0.310). Using UCd, ATL, sex, and age to construct the nomogram, and the C-statistics 0.584 (95%CI: 0.536 ~ 0.632) and 0.816 (95%CI: 0.781 ~ 0.851) were obtained by internal verification of the calibration curve, C-statistics revealed nomogram model validation was good and using decision curve analysis (DCA) confirmed a good predictive value of the nomogram models. In a nomogram model, ATL, UCd, sex, and age were detected as independent risk factors for renal function impairment, with UCd being the strongest predictor.

Peripheral blood mononuclear cell gene expression and cytokine profiling in patients with intermittent claudication who exhibit exercise induced acute renal injury.

BackgroundIntermittent claudication (IC) is a common manifestation of peripheral arterial disease. Some patients with IC experience a rise in Urinary N-acetyl-β-D-Glucosaminidase (NAG)/ Creatinine (Cr) ratio, a marker of renal injury, following exercise. In this study, we aim to investigate whether peripheral blood mononuclear cells (PBMC) from patients with IC who exhibit a rise in urinary NAG/ Cr ratio following exercise exhibit differential IL-10/ IL-12 ratio and gene expression compared to those who do not have a rise in NAG/ Cr ratio.MethodsWe conducted a single center observational cohort study of patients diagnosed with IC. Blood and urine samples were collected at rest and following a standardised treadmill exercise protocol. For comparative analysis patients were separated into those with any rise in NAG/Cr ratio (Group 1) and those with no rise in NAG/Cr ratio (Group 2) post exercise. Isolated PBMC from pre- and post-exercise blood samples were analysed using flow cytometry. PBMC were also cultured for 20 hours to perform further analysis of IL-10 and IL-12 cytokine levels. RNA-sequencing analysis was performed to identify differentially expressed genes between the groups.Results20 patients were recruited (Group 1, n = 8; Group 2, n = 12). We observed a significantly higher IL-10/IL-12 ratio in cell supernatant from participants in Group 1, as compared to Group 2, on exercise at 20 hours incubation; 47.24 (IQR 9.70–65.83) vs 6.13 (4.88–12.24), p = 0.04. 328 genes were significantly differentially expressed between Group 1 and 2. The modulated genes had signatures encompassing hypoxia, metabolic adaptation to starvation, inflammatory activation, renal protection, and oxidative stress.DiscussionOur results suggest that some patients with IC have an altered immune status making them ‘vulnerable’ to systemic inflammation and renal injury following exercise. We have identified a panel of genes which are differentially expressed in this group of patients.

Ginkgobiloba leaf extract mitigates cisplatin-induced chronic renal interstitial fibrosis by inhibiting the epithelial-mesenchymal transition of renal tubular epithelial cells mediated by the Smad3/TGF-\u03b21 and Smad3/p38 MAPK pathways

BackgroundOur previous study indicated that Ginkgo biloba leaf extract (EGb) could protect against cisplatin-induced acute kidney injury in rabbits. The present study aimed to determine the effects and potential molecular mechanisms of EGb on chronic renal interstitial fibrosis induced by cisplatin using in vivo and in vitro models.MethodsRats received a single dose of cisplatin on Day 1, and a subset of rats was intraperitoneally injected with EGb daily between Days 22–40. In vitro, HK-2 cells were treated with cisplatin, and a subset of cells was cultivated with EGb or SIS3 (Smad3 inhibitor) for 48 h. Renal function of rats was assessed by detecting the levels of serum creatinine (Scr), blood urea nitrogen (BUN) and urinary N-acetyl-β-D-glucosaminidase (NAG). Hematoxylin and eosin staining and Masson’s trichrome staining were used to evaluate the damage and fibrosis of renal tissue. Western blotting, immunohistochemistry and immunofluorescence were used to detect the protein levels of fibrosis-associated proteins and signaling pathway-related proteins. RT–qPCR analysis was used to examine the mRNA levels of related indicators.ResultsEGb significantly decreased the increased levels of Scr, BUN and urinary NAG and attenuated renal damage and the relative area of renal interstitial fibrosis induced by cisplatin. Additionally, EGb decreased the protein levels of α-SMA, Col I, TGF-β1, smad2/3, phosphorylated (p)-smad2/3, p38 MAPK, and p-p38 MAPK; the ratio of p-p38 MAPK/p38 MAPK; and the mRNA level of p38 MAPK in renal tissues induced by cisplatin. In agreement with in vivo studies, EGb significantly reduced the increased protein levels of these indicators. Additionally, EGb significantly reduced the increased protein levels of vimentin, TIMP-1, and CTGF, as well as the mRNA levels of α-SMA, vimentin, and TGF-β1, while it significantly increased the reduced E-cadherin protein level and the MMP-1/TIMP-1 ratio in HK-2 cells induced by cisplatin. It’s worth noting that the effects of SIS3 in changing the above indicators were similar to those of EGb.ConclusionOur study demonstrated that EGb improved cisplatin-induced chronic renal interstitial fibrosis, and its mechanisms were associated with inhibiting the epithelial-mesenchymal transition of renal tubular epithelial cells via the Smad3/TGF-β1 and Smad3/p38 MAPK pathways.

Combined detection of urinary biomarkers noninvasively predicts extent of renal injury in patients with early diabetic kidney disease with kidney qi deficiency syndrome: A retrospective investigation.

Incipient diagnosis and noninvasive forecasts using urinary biomarkers are important for preventing diabetic kidney disease (DKD) progression, but they are also controversial. Previous studies have shown a potential relationship between urinary tubular biomarkers (UTBs) and traditional Chinese medicine (TCM) syndrome in patients with DKD. Thus, we further evaluated the clinical significance of combined detection of urinary biomarkers in noninvasively predicting the extent of renal damage in patients with early DKD with kidney qi deficiency syndrome, and preliminarily explored the potential biological link between UTBs and TCM syndrome in DKD. We categorized 92 patients with Type 2 diabetes mellitus into three groups as follows: 20 patients with normoalbuminuria, 50 patients with microalbuminuria, and 22 patients with macroalbuminuria. We found that, in all groups, 24 hr urinary albumin (24hUAlb) and urinary albumin-to-creatinine ratio (UACR) showed stepwise and significant increases. Urinary cystatin C (UCysC), urinary N-acetyl-β-d-glucosaminidase (UNAG), and urinary retinol-binding protein (URBP) synchronously increased gradually, consistent with the degree of albuminuria in all groups. Moreover, 24hUAlb and UACR were positively correlated with UCysC, UNAG, and URBP, respectively. In 72 patients with Type 2 DKD with albuminuria, a positive correlation was observed between UNAG and URBP, UCysC was also positively correlated with UNAG and URBP, respectively. Additionally, TCM syndrome distributional characteristics in all patients were consistent with clinical manifestations of kidney qi deficiency syndrome. Therefore, the combined detection of UCysC, UNAG, URBP, and UAlb may be used as a practical clinical technique to noninvasively forecast the extent of renal injury in patients with early Type 2 DKD with kidney qi deficiency syndrome. UTBs may be one of the biological bases of the specific TCM syndromes in DKD.