N-acetyl-beta-D-glucosaminidase Research Articles

Combined evaluation of liver and kidney function improves prediction of clinical outcome in patients with chronic heart failure and reduced ejection fraction

Abstract Background/Introduction The liver and the kidneys are important organs for body homeostasis and are both affected by heart failure (HF) either by systemic venous congestion or hypoperfusion. Purpose We aimed to verify whether the Model for End-stage Liver Disease eXcluding International normalized ratio (MELD-XI), as well as a combination of cholestatic liver and kidney function tests carry prognostic value in patients with chronic HF with reduced ejection fraction (HFrEF). The liver parameters included alkaline phosphatase (ALP), gamma glutamyl-transpeptidase (GGT), and total bilirubin, while kidney parameters consisted of eGFR and the tubular damage markers urinary N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule (KIM)-1. Methods We categorized 250 patients with HFrEF on the basis of baseline biomarker levels. We assumed elevated NT-proBNP indicates hemodynamic congestion necessary to induce congestive liver or kidney dysfunction. Thus, in every organ damage category, NT-proBNP level above median was incorporated, next to any 2 out of 3: ALP, GGT or total bilirubin above median for liver dysfunction; any 2 out of 3 NAG or KIM-1 above median or eGFR below median for kidney dysfunction; or coexistence of liver and kidney dysfunction as defined above. Additionally, a subgroup of patients with both NT-proBNP and MELD-XI above the median was analyzed. The primary endpoint was a composite of cardiovascular death, heart transplantation, LVAD implantation, and hospitalization for acute or worsened HF, whichever occurred first. Univariable and multivariable Cox proportional hazard regression models were used. Results Median (Q1-Q3) age of the study population was 68 (58-76) years; 184 (74%) were men, 62 (25%) in NYHA class III or IV, and mean left ventricular ejection fraction (LVEF) was 31±9%. During a median (Q1-Q3) follow-up of 2.2 (1.4-2.5) years, 66 (26%) patients reached the primary endpoint. We observed that liver dysfunction, kidney dysfunction or their coexistence was associated with significantly higher risk of reaching the primary endpoint (HR 3.54, 95% CI 1.75–7.16; HR 1.85, 95% CI 1.00–3.41; HR 2.52, 95% CI 1.03–6.11 respectively) in the clinically adjusted model (Table 1). Higher MELD-XI was associated with higher risk of reaching the primary endpoint in an unadjusted model but not in a clinically adjusted model. Figure 1 presents event-free survival probability of patients falling into organ dysfunction categories. Conclusions Our results show that markers of cholestatic liver function and kidney function predict unfavorable clinical outcome and provide better prognostic value in chronic HFrEF patients than the MELD-XI alone. Thus, screening for liver and kidney damage may help identify high-risk patients in whom more careful observation and individualized therapy is warranted.Fig 1.Event-free survival probability

The Usefulness of Lordosis Load Test and Urinary Biochemistry in the Diagnosis of Orthostatic Proteinuria.

Introduction Renal disease is commonly suspected in patients with proteinuria. Renal biopsy might be considered based on the patient's clinical history and the results of diagnostic tests. However, as orthostatic proteinuria is benign and requires no treatment, it is important to obtain a diagnosis without renal biopsy whenever possible. Therefore, up to now, for the diagnosis of orthostatic proteinuria, in addition to resting urinalysis evaluation (disappearance of proteinuria), we have performed the lordosis load test and urine biochemistry of the samples showing peak proteinuria in a lordosis load test. Method We retrospectively enrolled all patients who visited the pediatric department and underwent the lordosis load test at Kanazawa Medical Center between 2011 and 2020. In the present study, samples with the highest concentrations of protein after the lordosis load test were subjected to general urinary biochemistry and urinary sediment analysis. Patients were followed up with the lordosis load test for several years. Results Enrolled in the study were 68 patients with OP. The mean age at the time of diagnosis was 11.5 years (range, six to 16 years). General urinary tests, urinary sediment, and urinary biochemistry including N-acetyl-beta-D-glucosaminidase (NAG), alpha1-microglobulin(α1MG), and beta 2-microglobulin (β2MG) were normal in all patients with orthostatic proteinuria except one case who was a premature baby. Conclusion If proteinuria disappears after two hours of rest, and urinary biochemistry of the samples showing peak proteinuria in the lordosis load test is normal, orthostatic proteinuria can be diagnosed more accurately.

Qualified kidney injury biomarkers demonstrate value during early clinical drug development.

Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n = 121), and (iv) healthy volunteers (n = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations.

Hong Guo Ginseng Guo (HGGG) protects against kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome and regulating intestinal flora

BackgroundDiabetic nephropathy (DN) is one of the most serious complications of diabetes which leads to end-stage renal failure and approximately one-third of patients need dialysis. There is still a lack of effective and specific treatment for DN. Searching new drugs from natural foods is an alternative approach to treat diabetes and its complications. Hong Guo Ginseng Guo (HGGG), a berry with palatability and nutritional benefits, has exhibited medicinal properties to mitigate the progression of DN. PurposeThis study investigates the effects of HGGG on streptozotocin (STZ)-induced diabetic nephropathy (DN) in rats and elucidates the mechanisms underlying its reno-protective and diabetes management benefits. MethodsThe LC-MS spectra method identified the primary ingredients in HGGG. To induce DN, male Sprague-Dawley (SD) rats received a single intraperitoneal injection of 75 mg/kg STZ. Over an eight-week treatment period, we assessed biochemical parameters including blood glucose, urine albumin-to-creatinine ratio (UACR), blood urea nitrogen (BUN), and urine N-acetyl-beta-d-glucosaminidase (NAG). Tissue pathology was examined using Masson's trichrome, Periodic Acid-Schiff (PAS), and Hematoxylin-Eosin (H&E) stains. We analyzed pro-inflammatory mediators and tissue fibrosis extent using Western blotting and immunohistochemistry. Gut microbiota composition was characterized via 16S rDNA sequencing. ResultsSeventeen chemical compounds were identified, with lobetyolin, luteolin, and rutin highlighted as the primary active elements. HGGG extract appeared to confer renal protection, demonstrated by improvements in UACR, BUN, and urine NAG levels. The reno protective effects in HGGG-treated DN rats were linked to reduced renal fibrosis and inhibition of the NLRP3 inflammasome. Additionally, HGGG administration improved gut barrier integrity and altered the gut microbiota in DN rats, increasing the relative abundance of beneficial bacteria known for regulating polyamines and producing short-chain fatty acids (SCFAs), including Ruminococcus, Barnesiella_sp, Anaerovoracaceae, and Prevotellaceae_NK3B31. Meanwhile, treatment with HGGG decreasing the presence of Oscillospira, potential pathogens responsible for producing lipopolysaccharide (LPS). ConclusionHGGG has potential as a beneficial fruit for managing diabetes and its associated complications through modulation of the gut microbiota.

Preliminary Results of Variation in Plasma N-acetyl-beta-D-glucosaminidase Concentration Among Bearded Dragons (Pogona vitticeps), Corn Snakes (Pantherophis guttatus), and Wood Turtles (Glyptemys insculpta)

Abstract N-acetyl-beta-D-glucosaminidase (NAG) is a lysosomal enzyme found in renal tubular epithelial cells whose concentration can be measured in blood as a possible diagnostic tool to monitor renal disease; however, no reference values are currently available in reptiles. This study investigated the presence of plasma NAG concentrations in 3 reptile species. Blood samples were obtained from clinically healthy bearded dragons (Pogona vitticeps; n = 13), corn snakes (Pantherophis guttatus; n = 9) and wood turtles (Glyptemys insculpta; n = 13). To further assess renal health, a biochemistry panel was performed for all animals, and renal biopsies were collected from the bearded dragons and snakes, but not from the turtles. Biopsies were not taken from wood turtles to limit the risk associated with anesthetizing an endangered species. Of the 35 animals sampled, 29 were considered healthy and included in the study. Plasma NAG concentrations in the wood turtles were significantly lower than in the corn snakes (P = 0.004) and plasma NAG concentrations in the corn snakes were significantly higher than in bearded dragons (P = 0.038). Wood turtles had the lowest NAG concentrations, followed by bearded dragons and corn snakes. In conclusion, NAG reference intervals should be established for each reptile species and analyte validation is needed for this assay in reptiles. Further research is needed to establish NAG reliability as a diagnostic tool in reptiles.

Role of urinary N-acetyl-beta-D-glucosaminidase in predicting the prognosis of antenatal hydronephrosis.

Urinary biomarkers are known to be able to diagnose renal damage caused by obstruction at an early stage. We evaluated the usefulness of urine N-acetyl-beta-D-glucosaminidase (NAG) to determine the prognosis of antenatal hydronephrosis. From January 2019 to December 2021, a retrospective study was performed on patients with grade 3 or 4 hydronephrosis. We analyzed the ultrasonographic findings and the urinary NAG/Cr ratio between the laparoscopic pyeloplasty (LP) group and active surveillance (AS) group. A total of 21 children underwent LP for ureteropelvic junction (UPJ) obstruction and 14 children underwent AS. The mean age at the time of examination was 3.7 months (1.7-7.5 months) in the LP and 5.2 months (0.5-21.5 months) in the AS (p=0.564). The mean anteroposterior pelvic diameter was 30.0 mm (15.0-49.0 mm) in the LP and 16.7 mm (9.0-31.3 mm) in the AS (p=0.003). The mean renal parenchymal thickness was 2.6 mm (1.2-3.7 mm) in the LP and 3.8 mm (2.9-5.5 mm) in the AS (p=0.017). The urinary NAG/Cr ratio was 26.1 IU/g (9.8-47.4 IU/g) in the LP and 11.1 IU/g (2.6-18.1 IU/g) in the AS (p=0.003). After LP, the urinary NAG/Cr ratio was significantly reduced to 10.4 IU/g (3.4-14.2 IU/g) (p=0.023). The urinary NAG/Cr ratio, one of the biomarkers of acute renal injury, is closely related to the degree of hydronephrosis. Therefore, it may be useful to determine whether to perform surgery on the UPJ obstruction and to predict the prognosis.

Melatonin prevents overproduction of reactive oxygen species and vascular dysfunction induced by cyclophosphamide

AimsOverproduction of reactive oxygen species (ROS) is a pathologic hallmark of cyclophosphamide toxicity. For this reason, antioxidant compounds emerge as promising tools for preventing tissue damage induced by cyclophosphamide. We hypothesized that melatonin would display cytoprotective action in the vasculature by preventing cyclophosphamide-induced oxidative stress. Materials and methodsMale C57BL/6 mice (22–25 g) were injected with a single dose of cyclophosphamide (300 mg/kg; i.p.). Mice were pretreated or not with melatonin (10 mg/kg/day, i.p.), given during 4 days before cyclophosphamide injection. Functional (vascular reactivity) and oxidative/inflammatory patterns were evaluated at 24 h in resistance arteries. The antioxidant action of melatonin was assessed in vitro in cultured vascular smooth muscle cells (VSMCs) of mesenteric arteries. Key findingsCyclophosphamide induced ROS generation in both mesenteric arterial bed (MAB) and cultured VSMCs, and this was normalized by melatonin. Cyclophosphamide-induced ROS generation and lipoperoxidation in the bladder and kidney was also prevented by melatonin. Increased levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were detected in the MAB of cyclophosphamide-treated mice, all of which were prevented by melatonin. Functional assays using second-order mesenteric arteries of cyclophosphamide-treated mice revealed a decrease in vascular contractility. Melatonin prevented vascular hypocontractility in the cyclophosphamide group. Melatonin partially prevented the decrease in myeloperoxidase (MPO) and N-acetyl-beta-D-glucosaminidase (NAG) activities in the MAB of the cyclophosphamide group. SignificanceMelatonin may constitute a novel and promising therapeutic approach for management of the toxic effects induced by cyclophosphamide in the vasculature.

Early decrease of ionized calcium and static symmetric dimethylarginine concentration in a model of renal tubular necrosis in corn snakes (Pantherophis guttatus).

To determine if plasma concentrations of symmetric dimethylarginine (SDMA), N-acetyl-beta-d-glucosaminidase (NAG), GGT, ALT, AST, lactate, total calcium, and ionized calcium (iCa) and the calcium:phosphorus ratio are clinically relevant biomarkers to detect early stages of tubular lesions in snakes. 6 adult corn snakes (Pantherophis guttatus). Corn snakes were administered 11 injections of gentamicin at 50 mg/kg, SC, q 24 h in an experimental model of induced tubular necrosis. Plasma biochemistry and blood gas analyses were performed at baseline and after the 3rd and 11th injections. Parameters were compared between time points using a paired Wilcoxon test. In 3 individuals, renal biopsies were collected at baseline before starting injections and at the 3rd and 11th injections, while renal tissue samples were procured after euthanasia in all individuals. Renal proximal and distal tubular necrosis and hepatic steatosis were present in all individuals at necropsy. Compared to baseline, decreased blood concentrations of lactate, ionized calcium, and total calcium and a decreased calcium:phosphorus ratio were noted. A significant decrease of lactate and ionized calcium was observed after 3 days. Conversely, no changes in SDMA, NAG, ALT, AST, GGT, and sodium were detected. Ionized calcium and lactate concentrations were the earliest parameters to decrease compared to baseline values in this experimental model. While SDMA is a sensitive indicator of renal disease in mammals, this biomarker did not increase in a model of induced acute tubular necrosis in corn snakes.

Diagnostic value of α1-MG and URBP in early diabetic renal impairment.

Aims/Introduction: Diabetic kidney disease (DKD) is defined as diabetes with impaired renal function, elevated urinary albumin excretion, or both. DKD is one of the most common microvascular complications of diabetes and plays an important role in the cause of end-stage renal disease (ESRD). About 5% of people with type 2 diabetes (T2DM) already have kidney damage at the time they are diagnosed, but other triggers of renal insufficiency, such as obesity, hyperlipidemia, glomerular atherosclerosis are often present, making it difficult to define "diabetic kidney disease" or "diabetic nephropathy" precisely in epidemiology or clinical practice. Therefore, the aim of this study is to identify diabetic patients with CKD at an early stage, and evaluate the value of tubular injury markers including α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), N-acetyl-beta-D-glucosaminidase (NAG) and Urinary retinol binding protein (URBP) in the development of diabetes to DKD. Materials and methods: We recruited a total of 182 hospitalized patients with T2DM in the First Affiliated Hospital of Zhengzhou University from February 2018 to April 2023. We collected basic clinical characteristics and laboratory biochemical parameters of the patients. Based on their levels of urinary albumin creatinine ratio (UACR) and glomerular filtration rate (GFR), patients were divided into DM group (UACR≤30mg/g and eGFR≥90mL/min/1.73m2, n = 63) and DKD group (UACR>30mg/g or eGFR<90mL/min/1.73m2, n = 119) excluding other causes of chronic kidney disease. We further developed diagnostic models to improve the ability to predict the risk of developing DKD by screening potential risk factors using univariate and multivariate logistic regression analysis. Calibration plots and curve analysis were used to validate the model and clinical usefulness. Next, we screened patients with relatively normal estimated glomerular filtration rate (eGFR) (≥90mL/min/1.73m2) to investigate whether tubular injury markers could accurately predict the risk of DKD in patients with normal renal function. We defined the rate of GFR decline as a prognostic indicator of renal function in patients and collected the information of the re-hospitalized DKD patients to determine whether the relevant indicators had an impact on the renal prognosis. Results: The patients with DKD had higher levels of tubular injury markers than patients with DM. URBP, α1-MG, eGFR were statistically different in both univariate and multivariate logistic regression analyses and displayed great predictive power after modeling with an area under curve of 0.987. The calibration curve showed medium agreement. Decision curve showed it would add more net benefits for clinical decision. After adjusting eGFR and serum creatinine (Scr), URBP was demonstrated to be associated with early renal function impairment. Conclusion: Tubular injury markers play an important role in early diabetic renal function impairment.

Urinary N-Acetyl-Beta-D-Glucosaminidase levels predict immunoglobulin a nephropathy remission status

BackgroundTubulointerstitial lesions play a pivotal role in the progression of IgA nephropathy (IgAN). Elevated N-acetyl-beta-D-glucosaminidase (NAG) in urine is released from damaged proximal tubular epithelial cells (PTEC) and may serve as a biomarker of renal progression in diseases with tubulointerstitial involvement.MethodsWe evaluated the predictive value of urinary NAG (uNAG) for disease progression in 213 biopsy-proven primary IgAN patients from January 2018 to December 2019 at Zhongshan Hospital, Fudan University. We compared the results with those of serum cystatin C (sCysC).ResultsIncreased uNAG and sCysC levels were associated with worse clinical and histological manifestations. Only uNAG level was independently associated with remission status after adjustment. Patients with high uNAG levels (> 22.32 U/g Cr) had a 4.32-fold greater risk of disease progression. The combination of baseline uNAG and clinical data may achieve satisfactory risk prediction in IgAN patients with relatively preserved renal function (eGFR ≥ 60 ml/min/1.73 m2, area under the curve [AUC] 0.760).ConclusionOur results suggest that uNAG is a promising biomarker for predicting IgAN remission status.

Sulfur quantum dots as a fluorescent sensor for N-acetyl-beta-D-glucosaminidase detection.

N-acetyl-beta-D-glucosaminidase (NAG) is an important biomarker for early clinical diagnosis of renal disease, suggesting the necessity to develop a fast and sensitive method for its detection. In this paper, we developed a fluorescent sensor based on polyethylene glycol (400) (PEG-400)-modified and H2O2-assisted etched sulfur quantum dots (SQDs). According to the fluorescence inner filter effect (IFE), the fluorescence of SQDs can be quenched by the p-nitrophenol (PNP) generated by NAG-catalyzed hydrolysis of p-Nitrophenyl-N-acetyl-β-D-glucosaminide (PNP-NAG). We successfully used the SQDs as a nano-fluorescent probe to detect the NAG activity from 0.4 to 7.5 U·L-1, with a detection limit of 0.1 U·L-1. Furthermore, the method is highly selective and was successfully used in the detection of NAG activity in bovine serum samples, suggesting its great application prospect in clinical detection.

Urinary cystatin C and N-acetyl-beta-D-glucosaminidase (NAG) as early biomarkers for renal disease in dogs with leishmaniosis

Canine leishmaniasis (CanL) is a disease caused by Leishmania infantum that can vary from a subclinical infection to a severe disease. Dogs affected with CanL present varying degrees of renal dysfunction. Unfortunately, traditional biomarkers such as urea and creatinine detect renal damage in advanced stages of the disease, so more accurate biomarkers are needed. Hence, we aimed to study how urinary cystatin C (CysC) and N-acetyl-beta-D-glucosaminidase (NAG), behave in dogs with CanL at different stages of the disease. Eighty-six CanL infected dogs were classified according to LeishVet stages: LI (16 dogs), LIIa (12 dogs), LIIb (12 dogs), LIII (16 dogs) and LIV (30 dogs); as a control, 17 healthy dogs were studied. Blood samples were collected for complete haematological and biochemistry analysis including plasma cystatin C. Urine analysis included urine specific gravity (USG), urine protein to creatinine ratio (UPC), CysC and NAG expressed as a ratio with creatinine uCysCc (μg/g) and uNAGc (IU/g). The haematological, biochemical and urinary analysis coincided with the LeishVet guidelines. The statistical study of the uCysCc ratio and the uNAGc, showed significant increase when compared against control starting from group LI (p < 0.05). Interestingly, when the cut-off values were calculated using the ROC curve, uCysCc (258.85 µg/g) and uNAGc (2.25 IU/g) 75 % of the dogs included in LI groups surpassed the threshold. Hence our study indicates that uCysCc and uNAGc, could help to detect early renal damage in CanL affected dogs.

Revisiting the Role of NAG across the Continuum of Kidney Disease.

Acute and chronic kidney diseases are an evolving continuum for which reliable biomarkers of early disease are lacking. The potential use of glycosidases, enzymes involved in carbohydrate metabolism, in kidney disease detection has been under investigation since the 1960s. N-acetyl-beta-D-glucosaminidase (NAG) is a glycosidase commonly found in proximal tubule epithelial cells (PTECs). Due to its large molecular weight, plasma-soluble NAG cannot pass the glomerular filtration barrier; thus, increased urinary concentration of NAG (uNAG) may suggest injury to the proximal tubule. As the PTECs are the workhorses of the kidney that perform much of the filtration and reabsorption, they are a common starting point in acute and chronic kidney disease. NAG has previously been researched, and it is widely used as a valuable biomarker in both acute and chronic kidney disease, as well as in patients suffering from diabetes mellitus, heart failure, and other chronic diseases leading to kidney failure. Here, we present an overview of the research pertaining to uNAG's biomarker potential across the spectrum of kidney disease, with an additional emphasis on environmental nephrotoxic substance exposure. In spite of a large body of evidence strongly suggesting connections between uNAG levels and multiple kidney pathologies, focused clinical validation tests and knowledge on underlining molecular mechanisms are largely lacking.

Oxymatrine Alleviates Gentamicin-Induced Renal Injury in Rats.

Gentamicin is an aminoglycoside antibiotic commonly used to treat Gram-negative bacterial infections that possesses considerable nephrotoxicity. Oxymatrine is a phytochemical with the ability to counter gentamicin toxicity. We investigated the effects and protective mechanism of oxymatrine in rats. The experimental groups were as follows: Control, Oxymatrine only group (100 mg/kg/d), Gentamicin only group (100 mg/kg/d), Gentamicin (100 mg/kg/d) plus Oxymatrine (100 mg/kg/d) group (n = 10). All rats were treated for seven continuous days. The results indicated that oxymatrine alleviated gentamicin-induced kidney injury, and decreased rats’ kidney indices and NAG (N-acetyl-beta-d-glucosaminidase), BUN (blood urea nitrogen) and CRE (creatine) serum levels. The oxymatrine-treated group sustained less histological damage. Oxymatrine also relived gentamicin-induced oxidative and nitrative stress, indicated by the increased SOD (superoxidase dismutase), GSH (glutathione) and CAT (catalase) activities and decreased MDA (malondialdehyde), iNOS (inducible nitric oxide synthase) and NO (nitric oxide) levels. Caspase-9 and -3 activities were also decreased in the oxymatrine-treated group. Oxymatrine exhibited a potent anti-inflammatory effect on gentamicin-induced kidney injury, down-regulated the Bcl-2ax and NF-κB mRNAs, and upregulated Bcl-2, HO-1 and Nrf2 mRNAs in the kidney tissue. Our investigation revealed the renal protective effect of oxymatrine in gentamicin-induced kidney injury for the first time. The effect was achieved through activation of the Nrf2/HO-1 pathways. The study underlines the potential clinical application of oxymatrine as a renal protectant agent for gentamicin therapy.

Comparison of the Effects of Sodium Valproate and Carbamazepine on Renal Function in Children With Epilepsy

Background: Renal disorders have been observed with the long-term treatment of some antiepileptic drugs (AEDs). We aimed to compare the effects of carbamazepine (CBZ) and valproate (VPA) on renal function in children with epilepsy. Methods: This quasi-experimental study included children with epilepsy aged 2 months to 14 years who had persistently been receiving CBZ or VLP monotherapy for more than 6 months and were referred to Bandar Abbas Children’s Hospital, Bandar Abbas, Iran, 2019-2020. Demographic features, including age and sex, as well as family history of epilepsy, disease duration, and duration of treatment were recorded for each patient. Random blood and urine samples, along with 24-hour urine samples were collected from all the participants. Blood urea nitrogen (BUN), sodium, alkaline phosphatase (ALP), and pH were measured in blood samples. Glucose, protein, sodium, potassium, phosphorus, and creatinine were estimated in 24-hour urine samples. N-acetyl-beta-D-glucosaminidase (NAG) and pH were assessed in random urine samples. Results: Of the 80 children in this study with a mean age of 7.43±3.22 years, 58 (72.5%) were males. Children in both groups were comparable in terms of age, sex, family history of epilepsy, and disease and treatment duration. The urine NAG level was significantly higher in the VPA group compared to the CBZ group (P=0.010). Further, 24-hour urine protein and glucose levels were significantly higher in the VPA group. As for blood parameters, except for sodium (P=0.034), ALP (P&lt;0.001), and pH (P=0.006) which were significantly higher in the CBZ group, other parameters were significantly higher in the VPA group. Conclusion: Overall, CBZ appears to be safer than VPA regarding its effects on renal function in children treated for epilepsy.

Sex-specific differences in early renal impairment associated with arsenic, lead, and cadmium exposure among young adultsin Taiwan.

Exposure to a single metal has been reported to damage renal function in humans. However, information regarding the association between multiple-metal exposure and markers for early renal impairment in different sexes among the young adult Taiwanese population is scarce. We assessed the association between exposure to arsenic (As), cadmium (Cd), and lead (Pb), and early renal impairment markers using urinary microalbumin (MA), β2-microglobulin (β2MG), and N-acetyl-beta-D-glucosaminidase (NAG) by analyzing 157 young adults aged 20‒29 years, in Taiwan. Inductively coupled plasma mass spectrometry was used to determine urinary As, Cd, and Pb levels. Regression models were applied to different sex groups. The results showed that after adjusting for potential confounding factors and each metal, urinary Cd levels were significantly positively associated with urinary MA (β = 0.523, 95% CI: 0.147–0.899) and β2MG (β = 1.502, 95% CI: 0.635–2.370) in males. However, the urinary Cd level was significantly positively associated with only urinary NAG (β = 0.161, 95% CI: 0.027–0.296) in females. This study thus indicates that the effect of exposure to metals (especially Cd) on early renal impairment among young adults in Taiwan is sex-specific. Our study results could contribute toward developing early intervention programs for decreasing the incidence of renal dysfunction. Further studies are warranted to confirm our findings and clarify the potential mechanisms involved.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11356-022-19521-3.

Role of urinary NAG enzyme in early detection of renal impairment in cystic fibrosis patients

BackgroundCystic fibrosis (CF) is the most common life-limiting autosomal recessive disease among people in the USA and Europe with increased prevalence in Egypt. Affected children are in danger of acute kidney injury and the development of chronic renal disease through exposure to multiple nephrotoxic agents. N-acetyl beta-D-glucosaminidase (NAG) is a lysosomal enzyme present in high concentrations in the proximal tubular cells, thus raising urinary NAG levels to reflect tubular dysfunction. The aim of our study is to detect the role of the urinary NAG enzyme in the early detection of renal impairment in CF patients. This cross-sectional study enrolled 40 CF patients diagnosed in the CF Clinic in Children’s Hospital of Cairo University. They were age- and sex-matched to 40 healthy controls. All patients had glomerular filtration rate (GFR), serum creatinine, blood urea nitrogen (BUN), albumin/creatinine (A/C) ratio measured, urine analysis, urinary NAG enzyme using enzyme-linked immunosorbent assay (ELISA), and renal ultrasound (U/S) were done.ResultsOur study showed high levels of urinary NAG in cases with a significant difference between cases and controls (P value < 0.001). There was a significant correlation between urinary NAG enzyme elevation and A/C ratio in urine, nephrotoxic drugs administration, and duration of disease (P value = 0.002, 0.005, 0.019), respectively.ConclusionOur study suggested that the NAG enzyme is a good early detector of renal impairment in CF patients before the conventional laboratory assays become deranged.

Böbrek taşı hastalarda ESWL’ ye bağlı renal hasar üzerine nar suyunun önleyici etkisi

Objective: We aimed to show whether the antioxidant properties of pomegranate juice (PJ) show a protective effect against renal damage associated with oxidative stress caused by Extracorporeal Shock Wave Lithotripsy (ESWL) in patients who have undergone ESWL for kidney stones. Material and Methods: Ninety patients who were to undergo ESWL for kidney stones were included in the study and were divided into 3 groups with 30 patients each ESWL. Group 1 (control group) patients received only ESWL treatment. Group 2 (study group) patients were recommended to take 30 ml/kg/day pomegranate juice mixture orally for 2 days before ESWL. Group 3 (placebo group) patients were recommended to take 30 mg/kg/day water orally for 2 days before ESWL. All ESWL-treated patients received 2000 to 2500 shock waves at 18 to 24 in order to measure lipid peroxidation markers showing the DNA lesion associated with oxidative stress and to show tubular damage after ESWL, Results: There was a statistically significant mean increase of 52.39± 10.49 in 8-Hydroxy deoxyguanosine (8-OHdG) levels after treatment compared to pre-treatment levels in Group 1 (p&lt;0.01). There was a statistically significant mean increase of 13.16±7.71 and 33.24±12.82 in Groups 2 and 3, respectively (p&lt;0.01; p&lt;0.01, respectively) There was a statistically significant mean increase of 19.20±5.21 in N-acetyl-beta-D-glucosaminidase (NAG) levels after treatment compared to pre-treatment levels in Group 1 (p&lt;0.01). There was a statistically significant mean increase of 3.44±5.21 and 13.07±5.50 in Groups 2 and 3, respectively (p&lt;0.01; p&lt;0.01, respectively). Conclusion: Our study concluded that pomegranate juice (PJ) has protective effects against ESWL-related renal damage. Keywords: Antioxidant, kidney stones, lithotripsy, pomegranate juice.

Exposure to an Extended-Interval, High-Dose Gentamicin Regimen in the Neonatal Period Is Not Associated With Long-Term Nephrotoxicity.

Objectives: To assess the association between gentamicin exposure and subclinical signs of nephrotoxicity in school children who were exposed to a high-dose gentamicin regimen in the neonatal period.Methods: Children receiving three or more doses (6 mg/kg) of gentamicin as neonates were invited to a follow-up in school age. We evaluated potential signs of subclinical nephrotoxicity with four validated urine biomarkers: protein-creatinine ratio (PCR), albumin-creatinine ratio (ACR), kidney injury molecule-1 (KIM-1), and N-acetyl-beta-D-glucosaminidase (NAG) normalized for urine creatinine (NAG-Cr). In addition, blood pressure was measured. The measures of gentamicin exposure were cumulative dose (mg/kg) and highest trough plasma concentration (TPC) in mg/L. We used logistic and linear regression and non-parametric kernel regression to analyze the relationship between gentamicin exposure and the urine biomarkers.Results: A total of 222 gentamicin exposed children were included. As neonates, the children were exposed to a median (interquartile range-IQR) cumulative gentamicin dose of 36 (26–42) mg/kg and the median (IQR) TPC was 1.0 (0.7–1.3) mg/L. At follow-up, 15 children (6.8%) had either one abnormal urine biomarker value (13 children) or two abnormal urine biomarker values (2 children). These 17 biomarker values were all marginally above the suggested upper cutoff, and included the following markers; KIM-1 (n = 2), NAC-Cr (n = 5), ACR (n = 6), and PCR (n = 4). All other 207 children had normal sets of all four urine biomarkers. One child had hypertension. There were no differences in gentamicin exposure, gestational age (GA) at birth or birth weight between the group of 15 children with one or two abnormal urine biomarker values compared to the other 207 children who had normal biomarker values. Using different regression analyses, we did not find any association between gentamicin exposure (cumulative dose and/or TPC) and the urine biomarker values.Conclusions: Exposure to an extended-interval, high-dose gentamicin regimen in the neonatal period was not associated with signs of subclinical nephrotoxicity in schoolchildren. We therefore suggest that the gentamicin treatment regimen evaluated in this study is safe in terms of long-term nephrotoxicity.Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03253614.

Peripheral mechanisms involved in Tityus bahiensis venom-induced pain

Scorpionism is a public health burden in Brazil. Tityus bahiensis is responsible for most accidents in the Southeastern region of Brazil. Here, the hyperalgesic mechanisms of Tityus bahiensis venom were investigated, focusing on the role of pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α] and interleukin 1 beta [IL-1β]) and activation of the transcription factor NFκB. Intraplantar (i.pl.) administration of Tityus bahiensis venom (0.2, 0.6, 1.2 and 2.4 μg/20 μL i.pl.) induced mechanical hyperalgesia and thermal hyperalgesia. The 2.4 μg dose of Tityus bahiensis venom induced overt pain-like behavior and increased myeloperoxidase (MPO) and N-acetyl-beta-D-glucosaminidase (NAG) activities, TNF-α and IL-1β levels in the paw tissue. Systemic pre-treatment with etanercept (soluble TNF-α receptor; 10 mg/kg), IL-1ra (IL-1 receptor antagonist; 30 mg/kg) and pyrrolidine dithiocarbamate (PDTC, nuclear factor kappa B [NFκB] inhibitor; 100 mg/kg) inhibited Tityus bahiensis venom-induced mechanical and thermal hyperalgesia, MPO and NAG activity and overt pain-like behavior. These data demonstrate the involvement of TNF-α and IL-1β signaling as well as NFκB activation in Tityus bahiensis venom-induced mechanical and thermal hyperalgesia, overt pain-like behavior, and MPO activity and NAG activity, indicating thus, that targeting these mechanisms might contribute to reducing the pain in this scorpionism.