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Background Many biomarkers show high diagnostic values for diabetic kidney disease (DKD), but fewer studies focus on the predictive assessment of DKD progression by blood and urinary biomarkers. Aim This study aims to find powerful risk predictors and identifying biomarkers in blood and urine for DKD progression. Methods A total of 117 patients with type 2 DKD including early and advanced stages and their laboratory parameters were statistically assessed. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the significance of discriminating between early and advanced DKD, and the predictive power for advanced DKD was analyzed by regression analysis and trisector grouping. Results N‐acetyl‐β‐d‐glucosaminidase‐creatine (NAG/CR) level in advanced DKD was statistically higher than that in early DKD (p < 0.05), and there was a higher incidence of advanced DKD (72% vs. 56%) and high odds ratio (OR: 3.917, 95% CI: 1.579–10.011) of NAG/CR with ≥2.79 U/mmol compared with <2.79 U/mmol (p < 0.05). NAG/CR ratio also showed a higher area under the ROC curve of 0.727 (95% CI: 0.616–0.828, p = 0.010) with a high sensitivity (0.75) and a moderate specificity (0.66) when 1.93 U/mmol was set as the optimal cutoff value. The adjusted‐multivariable analysis revealed that NAG/CR had an OR of 1.021 (95% CI: 1.024–1.038) and 2.223 (95% CI: 1.231–4.463) based on a continuous and categorical variable, respectively, for risk of advanced DKD. Moreover, the prevalence of advanced DKD exhibited an increasing tendency by an increment of the trisector of NAG/CR. Conclusions This study suggests that NAG/CR ratio is an independent predictor for advanced DKD, and it also can be used as a powerful identifying marker between early and advanced DKD. Regression analysis revealed urinary NAG/CR ratio is an independent risk predictor for advanced DKD, and ROC curve analysis showed it is a powerful indicator for discriminating between early and advanced DKD.

Erroneous conclusions may result from normalization of urine cadmium and N-acetyl-β-D-glucosaminidase concentrations ([Cd]u and [NAG]u) to the urine creatinine concentration ([cr]u). In theory, the sources of these errors are nullified by normalization of excretion rates (ECd and ENAG) to creatinine clearance (Ccr). We hypothesized that this alternate approach would clarify the contribution of Cd-induced tubular injury to nephron loss. We studied 931 Thai subjects with a wide range of environmental Cd exposure. For x = Cd or NAG, Ex/Ecr and Ex/Ccr were calculated as [x]u/[cr]u and [x]u[cr]p/[cr]u, respectively. Glomerular filtration rate (GFR) was estimated according to the Chronic Kidney Disease (CKD) Epidemiology Collaboration (eGFR), and CKD was defined as eGFR < 60 mL/min/1.73m2. In multivariable logistic regression analyses, prevalence odds ratios (PORs) for CKD were higher for log(ECd/Ccr) and log(ENAG/Ccr) than for log(ECd/Ecr) and log(ENAG/Ecr). Doubling of ECd/Ccr and ENAG/Ccr increased POR by 132% and 168%; doubling of ECd/Ecr and ENAG/Ecr increased POR by 64% and 54%. As log(ECd/Ccr) rose, associations of eGFR with log(ECd/Ccr) and log(ENAG/Ccr) became stronger, while associations of eGFR with log(ECd/Ecr) and log(ENAG/Ecr) became insignificant. In univariate regressions of eGFR on each of these logarithmic variables, R2 was consistently higher with normalization to Ccr. Our tabular and graphic analyses uniformly indicate that normalization to Ccr clarified relationships of ECd and ENAG to eGFR.

Cadmium (Cd) is a food-chain contaminant that has high rates of soil-to-plant transference. This phenomenon makes dietary Cd intake unavoidable. Although long-term Cd intake impacts many organ systems, the kidney has long been considered to be a critical target of its toxicity. This review addresses how measurements of Cd intake levels and its effects on kidneys have traditionally been made. These measurements underpin the derivation of our current toxicity threshold limit and tolerable intake levels for Cd. The metal transporters that mediate absorption of Cd in the gastrointestinal tract are summarized together with glomerular filtration of Cd and its sequestration by the kidneys. The contribution of age differences, gender, and smoking status to Cd accumulation in lungs, liver, and kidneys are highlighted. The basis for use of urinary Cd excretion to reflect body burden is discussed together with the use of urinary N-acetyl-β-d-glucosaminidase (NAG) and β2-microglobulin (β2-MG) levels to quantify its toxicity. The associations of Cd with the development of chronic kidney disease and hypertension, reduced weight gain, and zinc reabsorption are highlighted. In addition, the review addresses how urinary Cd threshold levels have been derived from human population data and their utility as a warning sign of impending kidney malfunction.

Human lysozyme is a natural non-specific immune protein that participates in the immune response of infants against bacterial and viral infections. Lysozyme is a well-known hydrolase that cleaves peptidoglycan in bacterial cell walls. Several crystal structures of human lysozyme have been reported, but little is known regarding how it recognizes sugar molecules. In this study, the crystal structures of human lysozyme in its native and two N-acetyl-α-d-glucosamine (α-D-NAG)-bound forms were determined at 1.3 Å and 1.55/1.60 Å resolution, respectively. Human lysozyme formed a typical c-type lysozyme fold and the α-D-NAG molecule was bound to the middle of subsites C and D. The N-acetyl and glucosamine groups of α-D-NAG were stabilized by hydrophobic interactions (Val117, Ala126, and Trp127), hydrogen bonds (Asn64, Asn78, Ala126, and Val128), and water bridges. Conformational changes of Arg80, Tyr81, Val128, and Arg131 of human lysozyme were observed due to the interactions of α-D-NAG with the active-site cleft. The binding configuration of α-D-NAG in human lysozyme was distinct compared with that of other sugar-bound lysozymes. Findings from this structural analysis provide a better understanding of the sugar recognition of human lysozyme during the immune response to microbial pathogens.

BACKGROUND: Urine protein loss is common in dogs with chronic kidney disease (CKD). HYPOTHESIS/OBJECTIVES: To evaluate new biomarkers of glomerular and tubulointerstitial (TI) damage compared with histology and as survival indicators in dogs with naturally occurring, proteinuric CKD. ANIMALS: One hunderd and eighty dogs with naturally occurring kidney disease. METHODS: Retrospective study using urine, serum, and renal biopsies from dogs with kidney disease, 91% of which had proteinuric CKD. Biomarkers were evaluated and correlated with pathologic renal damage, and significant associations, sensitivities, and specificities of biomarkers for renal disease type were determined. RESULTS: Fractional excretions of immunogloblin M (IgM_FE) and immunoglobulin G (IgG_FE) correlated most strongly with glomerular damage based on light microscopy (r = 0.58 and 0.56, respectively; P < .01). Serum creatinine (SCr) correlated most strongly with TI damage (r = 0.70, P < .01). Urine IgM/creatinine and urine NAG/creatinine had the highest sensitivity (75%) and specificity (78%) for detection of immune complex‐mediated glomerulonephritis. Although individually most biomarkers were significantly associated with decreased survival time (P < .05), in a multivariate analysis, SCr, IgM_FE, and glomerular damage based on transmission electron microscopy (TEM) were the only biomarkers significantly associated with survival time (SCr: P = .001; IgM_FE: P = .008; TEM: P = .017). CONCLUSIONS AND CLINICAL IMPORTANCE: Novel urine biomarkers and FEs are useful for detection of glomerular and TI damage in dogs with proteinuric CKD and might predict specific disease types and survival.

An enzyme with mannosyl glycoprotein endo-N-acetyl-β- d-glucosaminidase (ENGase)-type activity was partially purified from the extracellular medium of the mould Hypocrea jecorina (Trichoderma reesei). Internal peptides were generated and used to identify the gene in the T. reesei genome. The active enzyme is processed both at the N- and at the C-terminus. High-mannose-type glycoproteins are good substrates, whereas complex-type glycans are not hydrolysed. The enzyme represents the first fungal member of glycoside hydrolase family 18 with ENGase-type activity. Bacterial ENGases and the fungal chitinases belonging to the same family show very low homology with Endo T. Database searches identify several highly homologous genes in fungi and the activity is also found within other Trichoderma species. This ENGase activity, not coregulated with cellulase production, could be responsible for the extensive N-deglycosylation observed for several T. reesei cellulases.

Abstract Background Sensitive and specific biomarkers for early tubulointerstitial injury are lacking. Hypothesis The excretion of certain urinary proteins will correlate with the state of renal injury in dogs with chronic kidney disease. Animals Twenty-five male colony dogs affected with X-linked hereditary nephropathy (XLHN) and 19 unaffected male littermates were evaluated. Methods Retrospective analysis of urine samples collected every 2–4 weeks was performed. Urine proteins evaluated were retinol binding protein (uRBP/c), β2-microglobulin (uB2M), N-acetyl-β-d-glucosaminidase (uNAG/c), neutrophil gelatinase-associated lipocalin (uNGAL/c), and immunoglobulin G (uIgG/c). Results were correlated with serum creatinine concentration (sCr), glomerular filtration rate (GFR), urine protein : creatinine ratio, and histopathologic analysis of serial renal biopsies. Analytical validation was performed for all assays; uNAG stability was evaluated. Results All urinary biomarkers distinguished affected dogs from unaffected dogs early in their disease process, increasing during early and midstages of disease. uRBP/c correlated most strongly with conventional measures of disease severity, including increasing sCr (r = 0.89), decreasing GFR (r = −0.77), and interstitial fibrosis (r = 0.80), P < .001. However, multivariate analysis revealed age, sCr, uIgG/c, and uB2M, but not uRBP/c, as significant independent predictors of GFR (P < .05). Conclusions and Clinical Importance All urinary biomarkers were elevated before sCr increased, but typically after proteinuria developed in dogs with progressive glomerular disease because of XLHN. uRBP/c measurement might be promising as a noninvasive tool for diagnosis and monitoring of tubular injury and dysfunction in dogs.

In theory, the identification of the source of excreted cadmium (Cd) might elucidate the pathogenesis of Cd-induced chronic kidney disease (CKD). With that possibility in mind, we studied Thai subjects with low, moderate, and high Cd exposure. We measured urine concentrations of Cd, ([Cd]u); N-acetyl-β-d-glucosaminidase, a marker of cellular damage ([NAG]u); and β2-microglobulin, an indicator of reabsorptive dysfunction ([β2MG]u). To relate excretion rates of these substances to existing nephron mass, we normalized the rates to creatinine clearance, an approximation of the glomerular filtration rate (GFR) (ECd/Ccr, ENAG/Ccr, and Eβ2MG/Ccr). To link the loss of intact nephrons to Cd-induced tubular injury, we examined linear and quadratic regressions of estimated GFR (eGFR) on ECd/Ccr, eGFR on ENAG/Ccr, and ENAG/Ccr on ECd/Ccr. Estimated GFR varied inversely with both ratios, and ENAG/Ccr varied directly with ECd/Ccr. Linear and quadratic regressions of Eβ2MG/Ccr on ECd/Ccr and ENAG/Ccr were significant in moderate and high Cd-exposure groups. The association of ENAG/Ccr with ECd/Ccr implies that both ratios depicted cellular damage per surviving nephron. Consequently, we infer that excreted Cd emanated from injured tubular cells, and we attribute the reduction of eGFR to the injury. We suggest that ECd/Ccr, ENAG/Ccr, and eGFR were associated with one another because each parameter was determined by the tubular burden of Cd.

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.

Due to its role in the crustacean moulting process, N-acetyl-beta-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.