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

BACKGROUND: A 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-ß-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. METHODS: Medical 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. RESULTS: Of 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). CONCLUSION: Urinary 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.

Evaluation of N-acetyl-ß-D-glucosaminidase as a prognostic marker for diabetic nephropathy in type 2 diabetics: systematic review and meta-analysis.

OBJECTIVE: This review aimed to assess the utility of urinary N-acetyl-ß-D-glucosaminidase (uNAG) as a prognostic biomarker for nephropathy in patients with type 2 diabetes mellitus. METHODS: The search for relevant studies was conducted across multiple databases, including PubMed (Medline), EMBASE, LILACS, CENTRAL, IBECS, and gray literature. We employed a random effects model to calculate the standardized mean difference and 95% confidence interval. Furthermore, we assessed heterogeneity using Cochrane's Q test and Higgins' I2 statistics. RESULTS: This review included a total of 16 articles involving 1669 patients, with 13 being case-control studies and three being cohorts. The meta-analysis conducted across all studies revealed significant heterogeneity. However, subgroup analysis of four studies indicated that an increase in uNAG among normoalbuminuric patients was associated with the development of macroalbuminuria (DMP = - 1.47; 95% CI = - 1.98 to 0.95; p < 0.00001; I2 = 45%). Conversely, it did not demonstrate effectiveness in predicting the development of microalbuminuria (DMP = 0.26; 95% CI = - 0.08 to 0.60; p = 0.13; I2 = 17%). CONCLUSIONS: Elevated uNAG levels in normoalbuminuric patients may indicate an increased risk for the development of macroalbuminuria, but not microalbuminuria. However, the high heterogeneity observed among the studies highlights the necessity for further research to validate these findings.

Association between continuous glucose monitoring-derived glycemic control indices and urinary biomarkers of diabetic kidney disease: Hyogo Diabetes Hypoglycemia Cognition Complications study.

AIMS: Glomerular damage and proximal tubular damage play an important role in the pathogenesis of diabetic kidney disease. This study aimed to investigate the relationship between the urinary markers of proximal tubular injury, including urinary liver-type fatty acid-binding protein-to-creatinine ratio (uL-FABP/Cr) and urinary N-acetyl-ß-D-glucosaminidase-to-creatinine ratio (uNAG/Cr), and glycemic control status. METHODS: This cross-sectional study included 245 and 39 patients with type 2 diabetes mellitus (T2DM) and non-T2DM (NDM), respectively. The participants of this study were fitted with retrospective CGM, and glycemic control indices, such as time in range (TIR) and glycemia risk index (GRI), were calculated. RESULTS: The results were presented as medians (interquartile ranges). The uL-FABP/Cr was significantly higher in the microalbuminuria than in the normo-albuminuria group [4.2 (2.7-7.1) and 2.2 (1.4-3.4) µg/gCr, respectively, P < 0.001], while the uNAG/Cr in the normo-albuminuria group [6.3 (4.5-10.1) U/gCr] was significantly higher than that in the NDM group [5.3 (3.8-6.3) U/gCr, P = 0.048] but significantly lower than that in the microalbuminuria group [9.2 (6.4-11.1) U/gCr, P = 0.004]. The multivariate logistic regression analysis indicated that CGM-derived TIR was significantly associated with the urinary albumin-to-creatinine ratio [uAlb/Cr, odds ratio (OR) 0.985, 95% confidence interval (CI) 0.971-0.998, P = 0.029] and uNAG/Cr (OR 0.973, 95% CI 0.957-0.989, P = 0.001) independent of renal function. GRI was similarly associated with uAlb/Cr and uNAG/Cr. CONCLUSION: The findings of this study indicated that uNAG/Cr was elevated before albuminuria development and was associated with CGM-derived TIR and GRI.

Impact of Dapagliflozin on the Renal Function and Damage in Patients with Heart Failure with a Reduced Ejection Fraction.

Objective Whether or not the initial dip in the glomerular filtration rate (GFR) after the initiation of sodium-glucose co-transporter 2 inhibitors (SGLT2is) is associated with renal tubular injury in patients with heart failure with a reduced ejection fraction (HFrEF) is unclear. We therefore investigated the relationship between changes in the estimated GFR (eGFR) and urine N-acetyl-ß-D-glucosaminidase (uNAG) after the initiation of dapagliflozin in patients with HFrEF. Methods We prospectively investigated 89 patients with HFrEF who were newly started on dapagliflozin 10 mg/day. Changes in the eGFR and uNAG-to-creatinine ratio (uNAG/Cre) were evaluated at 2 weeks and 2 months after the initiation of dapagliflozin. Results The eGFR was decreased at 2 weeks but had not declined further by 2 months. The uNAG/Cre was increased at 2 weeks but had not increased further by 2 months. There was no correlation between the changes in the eGFR and uNAG/Cre (r=-0.022, p=0.853 at 2 weeks and r=0.078, p=0.538 at 2 months). The relative change in the systolic blood pressure, hematocrit, plasma volume, and N-terminal pro-brain natriuretic peptide (NT-proBNP) were correlated with the relative change in the eGFR. In a multiple linear regression analysis, the relative change in the eGFR at 2 weeks was significantly associated with NT-proBNP, and the relative change in the uNAG/Cre was significantly associated with the use of loop diuretics and the relative change in urine osmolality at 2 weeks. Conclusion A transient decrease in the eGFR after the initiation of dapagliflozin in patients with HFrEF was not generally associated with renal tubular injury and might have been the result of hemodynamic alteration.

N-acetyl-ß-D-glucosaminidase measurement on the freshwater amphipod Gammarus fossarum: development, biological variability and application in an ecotoxicological approach.

Due to its role in the crustacean moulting process, N-acetyl-ß-D-glucosaminidase (NAGase) is interesting to monitor the good proceeding of the moult cycle, as well as relevant in assessing changes in the moulting process caused by stressors. The present study aimed to measure the NAGase activity to monitor the moulting process of the freshwater amphipod Gammarus fossarum. Firstly, an optimised protocol measuring the NAGase activity was made, allowing a robustness and reproducibility of measurements. Then, intrinsic variability of NAGase response was checked under two physiological factors: the gammarid moult cycle and gender. For both genders, a significative increase of activity was observed during premoult, instead of a basal activity detected during postmoult and intermoult. However, the NAGase female profile was preconised to study since it was defined with more precision. Finally, a 16-day exposure of female gammarids to different levels of treated or non-treated wastewater effluents was made. If delays of tissue development appeared on effluent exposed specimens, NAGase activity was similar between the different conditions. This apparent desynchronization between tissue and molecular activities accentuates the diagnostic of moult impairment and raises the interest to use markers at different organisational levels.

Application of urinary N-acetyl-ß-D-glucosaminidase combined with serum retinol-binding protein in early detection of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a microangiopathy of type 2 diabetes mellitus (T2DM), which can damage the kidney through various ways and mechanisms due to the nature of the disease, involving the renal interstitium and glomeruli. However, in the early stage of the disease, patients only showed kidney volume increase and glomerular hyperthyroidism, and typical symptoms that are difficult to arouse individual attention were noticed. AIM: To observe the expression of serum retinol-binding protein (RBP) and urinary N-acetyl-ß-D-glucosaminidase (NAG) in patients with DN, and to analyze their value in disease prediction, so as to provide new targets for early diagnosis and treatment of DN. METHODS: The baseline data of 50 T2DM patients treated in our hospital between January 2021 and December 2022 were retrospectively reviewed and included in group A. The baseline data of 50 patients with type 2 DN admitted to our hospital during the same period were collected and included in group B. The baseline data and serum RBP and urine NAG expression were compared between the two groups to analyze their value in the early prediction of DN. RESULTS: There was no significant difference in age, gender, duration of diabetes, combined hyperlipidemia and combined hypertension between the two groups (P > 0.05); the expression of urinary NAG and serum RBP in group B was higher than that in group A, and the difference was statistically significant (P < 0.05); a multiple logistic regression model was established, and the results showed that urinary NAG and serum RBP were related to the presence or absence of injury in diabetic patients, and overexpression of urinary NAG and serum RBP may be risk factors for renal injury in T2DM patients (OR > 1, P < 0.05); receiver operating curve curve was plotted, and the results showed that the area under the curve of urinary NAG and serum RBP expression alone and in combination for predicting DN was > 0.80, and the predictive value was satisfactory; bivariate Spearman linear correlation analysis showed that there was a positive correlation between urinary NAG and serum RBP expression in patients with DN (r = 0.566, P = 0.000). CONCLUSION: The increased expression of urinary NAG and serum RBP may be the risk factors leading to the progression of T2DM to DN. The possibility of DN can be considered in patients with urinary NAG and serum RBP overexpression by examining the expression of urinary NAG and serum RBP in patients with T2DM in clinical practice.

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

BACKGROUND: Chronic 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. METHODS: We 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-ß-d-glucosaminidase (NAG). RESULTS: In 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). CONCLUSIONS: Our 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.

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

OBJECTIVE: 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. METHODS: 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-ß-d-glucosaminidase (NAG) and liver-type fatty acid-binding protein (l-FABP) for renal tubular dysfunctions. RESULTS: 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. CONCLUSIONS: 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.

Normal values for pediatric urinary biochemistry in early infancy.

BACKGROUND: Urinary levels of N-acetyl-ß-D-glucosaminidase (NAG), α1-microglobulin (α1-MG), and ß2-microglobulin (ß2-MG) are measured as markers of renal tubular damage. We previously determined normal values for these urine biochemical examinations in healthy children over 3 years old. However, the values are not applicable to children younger than 2 years old, and children less than 1 year old, in particular, seem to show very high levels for all these markers. Hence, as normal values for children below 2 years old remain unclear, we determined the normal values for urinary biochemical markers in this age group. MATERIAL AND METHODS: Fresh urine samples were obtained from 293 healthy children (from newborns to 2-year-old children). All the samples were subjected to normal urinalysis. NAG, α1-MG, ß2-MG, and creatinine (Cr) levels in extracted samples were measured immediately in the central laboratory at Kanazawa Medical Center. RESULTS: The normal values for each biomarker in children below 2 years of age were determined. Additionally, urinary α1-MG levels were observed to decrease most rapidly with age, almost reaching the level at ≥ 3 years by 6 months after birth. CONCLUSION: Renal tubular function can be evaluated in children < 3 years old using the normal values. Further, the most stable and useful urinary marker from early infancy seems to be urinary α1-MG.

Effects of Chemical Compounds on the Activity of the N-acetyl-ß-D-Glucosaminidase of the Marine Prawn, Palaemon serratus: Screening In Vitro.

N-acetyl-ß-D-glucosaminidase (NAGase) is important for crustaceans because the enzyme activity is necessary for the molting process. The present study aimed to assess the sensitivity of Palaemon serratus NAGase activity to a set of compounds of diverse chemical families in the context of in vitro exposures. Compounds representing different chemical families were selected according to their abundance, impact in the environment, and relevance as disruptors of the molting process. In a first step, four solvents (dimethylsulfoxide [DMSO], methanol, acetone, and ethanol) were tested to determine their suitability to dissolve hydrophobic compounds without affecting NAGase activity. Exclusively, ethanol had no effect on enzyme activity and on the integrity of the proteins present in the enzyme extract. The 18 other compounds were tested and four of these compounds, pentoxifylline, fenoxycarb, dithiocarbamate, and RH5849, showed a specific alteration on the activity of NAGase, without affecting the protein content. However, cadmium, zinc, and glyphosate showed a nonspecific alteration, affecting both the enzyme activity and the proteins, whereas ibuprofen exclusively altered the protein content. Finally, 10 of the 22 tested compounds (including DMSO, acetone, and methanol) showed a direct alteration of NAGase activity. Environ Toxicol Chem 2023;42:846-858. © 2023 SETAC.

Prediction of acute kidney injury after total aortic arch replacement with serum cystatin C and urine N-acetyl-ß-d-glucosaminidase: A prospective observational study.

BACKGROUND: Acute kidney injury (AKI) after total aortic arch replacement (TAAR) is frequent and associated with adverse outcomes, whereas its early detection remains a challenge. Serum cystatin C (sCysC) and urinary N-acetyl-ß-d-glucosaminidase (uNAG) are clinically available renal biomarkers, but their combination for AKI detection requires more evidence. This study aimed to assess the discriminative abilities of these biomarkers in AKI after TAAR. MATERIALS AND METHODS: Patients undergoing TAAR were included in this prospective observational study. The AKI prediction model was developed and internal verificated, and the significance of each variable was analyzed by random forest (RF). Finally, the best predictive critical values of sCysC and uNAG were explored by the AUC-ROC curve. RESULTS: The AUC-ROC of the prediction model was substantially enhanced by adding sCysC and uNAG (0.909 vs 0.844, p < 0.001), and the clinical utility and risk reclassification were significantly improved. Additionally, the RF showed that sCysC and uNAG ranked first and second. The AUC-ROC for each were 0.864 and 0.802 respectively, and the cut-off values were 1.395 mg/L and 31.90 U/g Cre respectively. CONCLUSION: The prediction model incorporating functional marker sCysC and tubular injury marker uNAG can improve the discriminative abilities of AKI after TAAR.

Prognostic Value of Urinary N-Acetyl-ß-d-Glucosaminidase as a Marker of Tubular Damage in Patients with Heart Failure and Mitral Regurgitation.

Background: Mitral regurgitation (MR) has a high prevalence and aggravates hypoperfusion and hypoxia in heart failure (HF). Renal tubular epithelial cells are sensitive to hypoxia, and therefore tubulointerstitial damage is quite common in HF. However, the correlation between tubular dysfunction and MR has not been studied. The aim of this work was to evaluate the prognostic significance of urinary N-acetyl- ß -d-glucosaminidase (uNAG), a biomarker of renal tubular damage, in patients with HF and MR. Methods: This was a prospective cohort study of 390 patients (mean age 64 years; 65.6% male) with uNAG measurement on admission (expressed as urinary NAG/urinary creatinine) and at least 1 year of follow-up data. The pre-defined primary endpoint was the composite of all-cause mortality or rehospitalization for HF after discharge. Cox regression analysis, restricted cubic splines, and subgroup analysis were used to investigate the prognostic value of uNAG modeled as a categorical (quartiles) or continuous (per SD increase) variable. Results: A total of 153 (39.23%) patients reached the composite endpoint over a median follow-up time of 1.2 years. The uNAG level correlated with the severity of HF and with the incidence of adverse events. In a multivariable Cox regression model, each SD (13.80 U/g ⋅ Cr) of increased uNAG was associated with a 17% higher risk of death or HF rehospitalization (95% confidence interval, 2-33%, p = 0.022), and a 19% higher risk of HF rehospitalization (p = 0.027). Subgroup analysis revealed the associations between uNAG and poor prognosis were only significant in younger patients ( ≤ 65 years) and in patients without obvious cardiovascular comorbidities. Conclusions: uNAG levels at admission were associated with the risk of adverse outcomes in patients with HF and MR. Additional studies are needed to further investigate the heart-kidney interaction.

The Validity of Benchmark Dose Limit Analysis for Estimating Permissible Accumulation of Cadmium.

Cadmium (Cd) is a toxic metal pollutant that accumulates, especially in the proximal tubular epithelial cells of kidneys, where it causes tubular cell injury, cell death and a reduction in glomerular filtration rate (GFR). Diet is the main Cd exposure source in non-occupationally exposed and non-smoking populations. The present study aimed to evaluate the reliability of a tolerable Cd intake of 0.83 µg/kg body weight/day, and its corresponding toxicity threshold level of 5.24 µg/g creatinine. The PROAST software was used to calculate the lower 95% confidence bound of the benchmark dose (BMDL) values of Cd excretion (ECd) associated with injury to kidney tubular cells, a defective tubular reabsorption of filtered proteins, and a reduction in the estimated GFR (eGFR). Data were from 289 males and 445 females, mean age of 48.1 years of which 42.8% were smokers, while 31.7% had hypertension, and 9% had chronic kidney disease (CKD). The BMDL value of ECd associated with kidney tubular cell injury was 0.67 ng/L of filtrate in both men and women. Therefore, an environmental Cd exposure producing ECd of 0.67 ng/L filtrate could be considered as Cd accumulation levels below which renal effects are likely to be negligible. A reduction in eGFR and CKD may follow when ECd rises from 0.67 to 1 ng/L of filtrate. These adverse health effects occur at the body burdens lower than those associated with ECd of 5.24 µg/g creatinine, thereby arguing that current health-guiding values do not provide a sufficient health protection.

Associations of urinary orosomucoid, N-acetyl-ß-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-ß-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.

What is the context? There is a relationship between high blood pressure and cardiovascular and kidney disease. Hypertension is defined as the level of blood pressure at which the benefits of treatment outweigh the risks of treatment. Hypertension is a risk factor for developing kidney disease, and kidney disease is a risk factor for developing hypertension. Today, kidney function is assessed by blood and urine samples (estimated glomerular filtration rate and urinary albumin excretion). However, today's blood and urine samples are not sensitive enough to capture kidney damage due to hypertension at a stage when prevention may be most effective.What is new? In this study, we assessed if urine orosomucoid and N-acetyl-ß-D-glucosaminidase (NAG) are more strongly associated with blood pressure and hypertension than urinary albumin excretion. In the population-based study of residents in Tromsø, Northern Norway, we assessed the relationship between the urine biomarkers and blood pressure, and the development of hypertension after 7 years. In the general population urine orosomucoid had a stronger relationship with blood pressure than urinary albumin excretion. After 7 years, urine orosomucoid had the strongest relationship with the development of hypertension. There were only varying and weak relationships between NAG, blood pressure and hypertension.What is the impact? Orosomucoid showed a stronger relationship with blood pressure and the development of hypertension than urinary albumin excretion. Urine orosomucoid may aid targeted prevention and treatment in hypertension, but further prospective clinical studies are needed to assess if orosomucoid is a clinically useful biomarker in hypertension.

Dose-Response Analysis of the Tubular and Glomerular Effects of Chronic Exposure to Environmental Cadmium.

We retrospectively analyzed data on the excretion of cadmium (ECd), ß2-microglobulin (Eß2M) and N-acetyl-ß-D-glucosaminidase (ENAG), which were recorded for 734 participants in a study conducted in low- and high-exposure areas of Thailand. Increased Eß2M and ENAG were used to assess tubular integrity, while a reduction in the estimated glomerular filtration rate (eGFR) was a criterion for glomerular dysfunction. ECd, Eß2M and ENAG were normalized to creatinine clearance (Ccr) as ECd/Ccr, Eß2M/Ccr and ENAG/Ccr to correct for interindividual variation in the number of surviving nephrons and to eliminate the variation in the excretion of creatinine (Ecr). For a comparison, these parameters were also normalized to Ecr as ECd/Ecr, Eß2M/Ecr and ENAG/Ecr. According to the covariance analysis, a Cd-dose-dependent reduction in eGFR was statistically significant only when Ecd was normalized to Ccr as ECd/Ccr (F = 11.2, p < 0.001). There was a 23-fold increase in the risk of eGFR ≤ 60 mL/min/1.73 m2 in those with the highest ECd/Ccr range (p = 0.002). In addition, doubling of ECd/Ccr was associated with lower eGFR (ß = -0.300, p < 0.001), and higher ENAG/Ccr (ß = 0.455, p < 0.001) and Eß2M/Ccr (ß = 0.540, p < 0.001). In contrast, a covariance analysis showed a non-statistically significant relationship between ECd/Ecr and eGFR (F = 1.08, p = 0.165), while the risk of low eGFR was increased by 6.9-fold only among those with the highest ECd/Ecr range. Doubling of ECd/Ecr was associated with lower eGFR and higher ENAG/Ecr and Eß2M/Ecr, with the ß coefficients being smaller than in the Ccr-normalized dataset. Thus, normalization of Cd excretion to Ccr unravels the adverse effect of Cd on GFR and provides a more accurate evaluation of the severity of the tubulo-glomerular effect of Cd.

Correlation between albuminuria and interstitial injury marker reductions associated with SGLT2 inhibitor treatment in diabetic patients with renal dysfunction.

BACKGROUND: We investigated the effects of sodium-glucose cotransporter 2 inhibitor (SGLT2i) administration focusing on its involvement in tubulo-interstitial disorders in diabetic kidney. METHODS: Enrolled patients with diabetic kidney disease received a mean dose of 52.3 mg of an SGLT2i (ipragliflozin) daily. Blood and urine were sampled at 0, 1, and 12 months (M). RESULTS: Non-renal-dysfunction patients (NRD: baseline eGFR ≥ 60 mL/min/1.73 m2, n = 12) and renal-dysfunction patients (RD: baseline eGFR < 60 mL/min/1.73 m2, n = 9) were analyzed separately. The median urine albumin-to-Cr ratio (ACR) was significantly decreased at 1 M in both groups (NRD: 163.1 at 0 M vs 118.5 mg/g Cr at 1 M, RD: 325.2 at 0 M vs 136.0 mg/g Cr at 1 M). In the RD, but not the NRD group, reduction of urine monocyte chemotactic protein-1 (MCP-1) by SGLT2i showed a significant difference between high-responders (HR: - 25.7 ± 11.4%) and low-responders (LR: 59.2 ± 17.0%), defined by ACR reduction at 1 M. Univariate analysis showed a significant correlation between the reduction of ACR and MCP-1 (R = 0.683, p = 0.042) in RD. CONCLUSION: SGLT2i exerted an anti-albuminuric effect regardless of the presence/absence of renal dysfunction. However, the anti-albuminuric effect of SGLT2i in patients with renal dysfunction appears more closely associated with amelioration of tubulo-interstitial disorders compared to patients without renal dysfunction.

High Glycated Hemoglobin Instead of High Body Mass Index Might Increase the Urine N-Acetyl-ß-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-ß-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 Malondialdehyde (MDA) and N-Acetyl-ß-D-Glucosaminidase (NAG) Associated with Exposure to Trichloroethylene (TCE) in Underground Water.

Trichloroethylene (TCE) is commonly used in various industries. If wastewater in factories is not effectively treated, the inflow into and subsequent contamination of underground water is likely. Our study assessed the association of exposure to TCE in underground water with oxidative stress and renal tubule damage. We selected 579 residents from areas with underground water contaminated with TCE. Each participant was interviewed via a questionnaire. We also assessed their urinary trichloroacetic acid (TCA) levels by gas chromatography (GC)-FID. Urinary malondialdehyde (MDA) and N-acetyl-ß-D-glucosaminidase (NAG) were taken as indicators of oxidative stress and renal tubule damage. We found about 73% of the residents to have consumed underground water. The average duration of consumption was 26 years, with an average of 1.6 L per day. Currently, only 1.5% of the residents still continuously consume underground water. The consumption of underground water positively correlated with heightened urinary TCA levels (r = 0.554). Heightened urinary TCA levels, in turn, were positively associated with NAG levels (r = 0.180) but negatively associated with MDA levels (r = -0.193). The results held even after we had segmented urinary TCA levels into three groups of different levels. The elimination of the source of heightened TCE levels from various industrial effluents is essential. Residents exposed to TCE-laden underground water should periodically undergo health inspections.

Current knowledge about biomarkers of acute kidney injury in liver cirrhosis.

Acute kidney injury (AKI) is common in advanced cirrhosis. Prerenal azotemia, hepatorenal syndrome, and acute tubular necrosis are the main causes of AKI in patients with cirrhosis. Evaluation of renal function and differentiation between functional and structural kidney injury are important issues in the management of cirrhosis. However, AKI in cirrhosis exists as a complex clinical spectrum rather than concrete clinical entity. Based on current evidence, changes in serum creatinine (Cr) levels remain the most appropriate standard for defining AKI in cirrhosis. However, serum Cr has a limited role in assessing renal function in this population. This review examines previous studies that investigated the ability of recent biomarkers for AKI in cirrhosis from the perspective of earlier and accurate diagnosis, classification of AKI phenotype, and prediction of clinical outcomes. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin have been extensively studied in cirrhosis, and have facilitated improved diagnosis and prognosis prediction in patients with AKI. In addition, urine N-acetyl-ß-D-glucosaminidase, interleukin 18, and kidney injury molecule 1 are other promising biomarkers for advanced cirrhosis. However, the clinical significance of these markers remains unclear because there are no cut-off values defining the normal range and differentiating phenotypes of AKI. In addition, AKI has been defined in terms of serum Cr, and renal biopsy-the gold standard-has not been carried out in most studies. Further discovery of innovate biomarkers and incorporation of various markers could improve the diagnosis and prognosis prediction of AKI, and will translate into meaningful improvements in patient outcomes.

The Role of Urinary N-Acetyl-ß-d-glucosaminidase in Cirrhotic Patients with Acute Kidney Injury: Multicenter, Prospective Cohort Study.

BACKGROUND AND AIMS: Currently, it is difficult to predict the reversibility of renal function and to discriminate renal parenchymal injury in cirrhotic patients with acute kidney injury (AKI). The aim of this study is to evaluate whether urine N-acetyl-ß-d-Glucosaminidase (NAG) can predict the survival and response to terlipressin in cirrhotic patients with AKI. METHODS: Two hundred sixty-two cirrhotic consecutive patients who developed AKI were prospectively enrolled from 11 tertiary medical centers in Korea between 2016 to 2019. AKI was defined as an increase in serum Cr (SCr) of 0.3 mg/dL or a 50% increase in baseline SCr. Patients diagnosed with hepatorenal syndrome (HRS-AKI) were treated with terlipressin plus albumin. RESULTS: The patients were 58.8 ± 12.9 years old on average and were predominantly male (72.5%). The mean MELD score was 25.3 ± 9.1. When classified according to the AKI phenotype, there were 119 pre-renal, 52 acute tubular necrosis, 18 miscellaneous, and 73 HRS-AKI patients. However, the urine NAG was not effective at discriminating AKI phenotypes, except for HRS-AKI. The baseline urine NAG increased as the baseline AKI stage increased (p < 0.001). In addition, within the same AKI stage, the urine NAG values were significantly lower in the AKI-resolved group than in the unresolved group. The urine NAG level was significantly lower in living patients compared with those who died or who underwent a liver transplant within 3 months (p = 0.005). In the multivariate analysis, the increased urine NAG was a significant risk factor for the 3-month transplant-free survival (TFS) rate, especially in patients with Child-Pugh class ≤ B or MELD < 24. The urine NAG did not predict the response to terlipressin treatment in patients with HRS. CONCLUSIONS: Urine NAG is strongly associated with the severity of AKI in patients with liver cirrhosis and is useful for predicting the 3-month TFS.