Predictive value of novel biomarkers for chronic kidney disease among workers occupationally exposed to silica.

There is a pressing need to find reliable biomarkers for the early diagnosis of silica-induced nephropathy. Abundant genes are upregulated in damaged kidneys with subsequent protein products appearing in the urine. Liver-type fatty acid-binding protein (L-FABP) and kidney injury molecule-1 (KIM-1) are among the most promising. Our objective was to study the importance of L-FABP and KIM-1 genes and their urinary proteins in the early detection of silica-induced renal injury, as compared with other conventional biomarkers. A cross-sectional study was conducted among 90 pottery workers occupationally exposed to silica, as compared to 90 controls. A full history taking and complete clinical examination were performed. Levels of serum creatinine, liver enzymes, urinary silicon, KIM-1, and L-FABP gene expression and protein products were measured. Estimated glomerular filtration rate (eGFR) was calculated, and abdominal ultrasound was performed. The results showed that the silica-exposed group had a statistically significant increase in serum creatinine and urinary silica, as well as a significant decrease in eGFR. Additionally, a significant increase in KIM-1 and L-FABP gene expression, associated with a significant increase in their urinary protein, was found among the exposed group. A positive correlation between urinary silica level and L-FABP gene expression was also found. A receiver operating characteristic curve analysis for L-FABP and KIM-1 gene as predictors for silica-induced nephropathy showed that L-FABP gene and protein specificity were greater than the KIM-1 gene and protein. Taken together, these findings suggest that the L-FABP gene and its protein product may be used as early indicators for renal injury among silica exposed workers.

Oral intake of mesoporous silica is safe and well tolerated in male humans.

BACKGROUND: Precisely engineered mesoporous silica has been shown to induce weight loss in mice, but whether it is safe to use in humans have not investigated. OBJECTIVE: The aim was to determine whether oral dosing, up to 9 grams/day, of precisely engineered mesoporous silica as a food additive can be used safely in male humans. DESIGN: This single blinded safety study consisted of two study arms including 10 males each (18-35 years). One arm consisted of participants with normal weight and one with obesity. After a placebo run-in period, all subjects were given porous silica three times daily, with increasing dose up to 9 grams/day (Phase 1). Subjects with obesity continued the study with highest dose for additional 10 weeks (Phase 2). RESULTS: All participants completed Phase 1 and 90% completed Phase 2, with approximately 1% missed doses. Participants reported no abdominal discomfort, and changes in bowel habits were minor and inconsistent. The side effects observed were mild and tolerable, biomarkers did not give any safety concern, and no severe adverse events occurred. CONCLUSION: Mesoporous silica intake of up to 9 grams/day can be consumed by males without any major adverse events or safety concerns.

Demonstration of Subclinical Early Nephrotoxicity Induced by Occupational Exposure to Silica among Workers in Pottery Industry.

BACKGROUND: For many years, several studies drew attention to the possible nephrotoxic effects of silica and distinct renal dysfunction involving glomerular and renal tubules in workers exposed to silica. OBJECTIVE: To determine the early signs of subclinical nephrotoxic effects among some Egyptian workers exposed to silica in the pottery industry. METHODS: This study was carried out in El-Fawakhir handicraft pottery area, in Greater Cairo, Egypt. The studied population included 29 non-smoking male workers occupationally exposed to silica in addition to 35 non-smoking administrative male subjects who represented the comparison group in the study. Measured urinary parameters were concentrations of total protein (TP), microalbumin (Malb), activities of alkaline phosphatase (ALP), γ-glutamyl transferase (γ-GT), lactate dehydrogenase (LDH), kidney injury molecule-1 (KIM-1), and silicon (Si). RESULTS: Silica-exposed workers showed significantly (p<0.05) increased levels of urinary TP, Malb, ALP, γ-GT, LDH, and KIM-1 compared with the comparison group. Among the silicaexposed group, increased urinary Si levels were positively and significantly correlated (Spearman's ρ>0.60, p<0.001 for all variables) with the elevated urinary proteins (including KIM-1) and enzymes levels. All measured urinary parameters were positively and significantly correlated (ρ>0.75, p<0.001 for all variables) with the duration of work among exposed subjects. No significant correlation was observed between the measured variables and the age of workers. CONCLUSION: There is associated subclinical glomerular and tubular affection among silica exposed workers, which is related to the duration and intensity of exposure.

In vitro and in vivo evaluation of degradation, toxicity, biodistribution, and clearance of silica nanoparticles as a function of size, porosity, density, and composition.

Silica nanoparticles (SiO2 NPs) have potential utility in controlled release. Despite significant research in this area, there is a gap in the understanding of the correlation between SiO2 NP physicochemical properties on the one hand and their degradation in solutions, in cells, and in vivo on the other. Here, we fabricated SiO2 NPs with variations in size, porosity, density, and composition: 100 nm Stöber, 100 and 500 nm mesoporous, 100 nm disulfide-based mesoporous, and 100 nm disulfide-based hollow mesoporous. Degradation profiles over 28 days were investigated in simulated biological fluids and deionized water. Results show Meso 100, and 500 nanoparticles degraded faster at higher pH values. Results from macrophages indicate Meso 100 nanoparticles showed the highest degradation amount (~3.8%). Cytotoxicity evaluation of the particles in Human Aortal Endothelial Cells (HAECs) shows concentration-dependent toxicity for the particles. Results from CD-1 mice show ~53% of Meso 100 nanoparticles (25 mg kg-1) degraded and were detected in urine after seven days. It was shown nanoparticle porosity and composition as well as pH and ionic strength of the medium play the predominant roles for degradation of SiO2 NPs. Based on histological evaluations, at the injected doses investigated, the particles did not show toxicity.

In vivo study on the biodistribution of silica particles in the bodies of rats.

BACKGROUND: Biodegradable carrier materials with nontoxic degradation products are very valuable for delivering drugs and biologically active molecules. Many organic systems (such as liposomes, micelles and polymeric nanoparticles) and inorganic systems (metal oxides and silica) have been researched for delivering active substances to organs. Silica seems to be one of the most interesting and promising materials. OBJECTIVES: The aim of this study was to investigate the SiO2 elimination process from rats' organisms and to ascertain the distribution and prospective accumulation sites of the silica particles. MATERIAL AND METHODS: A suspension of silica particles (Ø 150 nm) in 0.9% NaCl solution was introduced into rats' circulatory system. The degradation of these particles over time and their accumulation in the heart, lungs, kidneys and liver were observed. RESULTS: It was found that 36% of the introduced silica particles were excreted with urine after four days. The remaining particles were accumulated in the kidneys and lungs, probably in the lung air sacs and kidney glomerulus. CONCLUSIONS: Silica seems to be promising carrier material. Silica particles dissolve in the rat's body and are eliminated in urine.

Study of kidney dysfunction in non-silicotic Egyptian workers.

Occupational exposure to silica dust could lead to renal alterations in the glomeruli and proximal tubules. In the present study, occupational exposure to silica dust has been examined as a possible risk factor with respect to subclinical signs of kidney dysfunction. One-hundred forty eight exposed workers from a ceramic factory versus 121 controls of matched age, socioeconomic status and smoking habits were included. Data was collected through a questionnaire and clinical examination. There was a high prevalence of renal complaints in the ceramic workers specially the loin pain, dysuria. Crystalluria was significantly higher in the exposed group (12.2%) than the controls (5%). Renal urinary biomarkers including the high-molecular-weight protein albumin (U.Malb); the low-molecular-weight protein α1-microglobulin (α(1)M); the lysosomal enzyme N-acetyl-ß-D-glucosaminidase (NAG) urinary excretion of copper (U.Cu) and zinc (U.Zn) have been investigated. Urinary levels of silica and creatinine (U.cr) were estimated. Data from the present study showed a high significant increase in the urinary excretion of all measured urinary parameters in the group of ceramic workers compared with control subjects. There were no significant differences in the means of U.Zn/U.cr, U.Malb/U.cr, and α(1)M/U.cr among the four investigated departments of ceramic factory. The significant difference was present mainly between the individual departments and the controls, while, there was significant differences in the means of U.Cu/U.cr, U.NAG/U.cr, and U.silica/U.cr among the four departments and the controls. Among the exposed workers, significant correlation was apparent between work duration and only U.Zn/U.cr (r=0.17, p<0.05), and U.Cu/U.cr (r=0.19, p<0.05), while all measured urinary parameters were significantly correlated with each other. On conclusion silica exposure leads to renal alterations which parallel the change in proteinuria and enzymuria, as well as the increased loss in urine of each of Zn and Cu. Measurement of the levels of urinary zinc and copper may serve as a sensitive indicator of the impaired renal function caused by silica exposure. The corresponding analytes could have potential value as indicators of renal function before the kidney is irreversibly injured and, thus could be suitable as monitoring tools for at-risk persons exposed to silica. Researches should assess whether the current occupational standards for silica adequately protect workers from renal disease or this established standard needs to be revised.

Fluorescent silica nanoparticles with efficient urinary excretion for nanomedicine.

The development of molecularly targeted probes that exhibit high biostability, biocompatibility, and efficient clearance profiles is key to optimizing biodistribution and transport across biological barriers. Further, coupling probes designed to meet these criteria with high-sensitivity, quantitative imaging strategies is mandatory for ensuring early in vivo tumor detection and timely treatment response. These challenges have often only been examined individually, impeding the clinical translation of fluorescent probes. By simultaneously optimizing these design criteria, we created a new generation of near-infrared fluorescent core-shell silica-based nanoparticles (C dots) tuned to hydrodynamic diameters of 3.3 and 6.0 nm with improved photophysical characteristics over the parent dye. A neutral organic coating prevented adsorption of serum proteins and facilitated efficient urinary excretion. Detailed particle biodistribution studies were performed using more quantitative ex vivo fluorescence detection protocols and combined optical-PET imaging. The results suggest that this new generation of C dots constitutes a promising clinically translatable materials platform which may be adapted for tumor targeting and treatment.

Subclinical nephrotoxicity associated with occupational silica exposure among male Kenyan industrial workers.

OBJECTIVE: To determine early signs of renal injury due to occupational silica exposure. DESIGN: Cross-sectional analytical research. SETTINGS: Kenyatta National Hospital for the referent population and Clayworks ceramics, bricks and tiles factory for the assessment of occupational silica exposure. SUBJECTS: Thirty three non-smoking silica-exposed male industrial workers and 38 non-smoking male referents participated in this study. RESULTS: Silica-exposed males excreted significantly increased levels of U.TP, U.Malb, U.ALP, U.y-GT and U.LDH compared to referent males. Among the silica-exposed males, U.Si negatively correlated significantly with age, U.TP correlated significantly to each of U.ALP and U.LDH. However, no correlation was observed between work duration and U.Si. CONCLUSION: The present study shows that there is associated glomerular and proximal tubular damage among silica exposed workers which is not duration related and is seemingly subclinical and nonprogressive and urinary silica levels appears to be similar in all groups and are not affected by exposure and work duration: the reason for which is unclear.

In vivo study of biodistribution and urinary excretion of surface-modified silica nanoparticles.

The biodistribution and urinary excretion of different surface-modified silica nanoparticles (SiNPs) in mice were investigated in situ using an in vivo optical imaging system. Three types of surface-modified SiNPs, including OH-SiNPs, COOH-SiNPs, and PEG-SiNPs with a size of approximately 45 nm, have been prepared with RuBPY doped for imaging purposes. Intravenous (i.v.) injection of these SiNPs followed by fluorescence tracing in vivo using the Maestro in vivo imaging system indicated that OH-SiNPs, COOH-SiNPs, and PEG-SiNPs were all cleared from the systemic blood circulation, but that both the clearance time and subsequent biological organ deposition were dependent on the surface chemical modification of the SiNPs. Thus, for instance, the PEG-SiNPs exhibited relatively longer blood circulation times and lower uptake by the reticuloendothelial system organs than OH-SiNPs and COOH-SiNPs. More interestingly, in vivo real-time imaged dominant signal in bladder and urine excretion studies revealed that all three types of i.v.-injected SiNPs with a size of approximately 45 nm were partly excreted through the renal excretion route. These conclusions were further confirmed through ex vivo organ optical imaging and TEM imaging and energy-dispersed X-ray spectrum analysis of urine samples. These findings would have direct implications for the use of SiNPs as delivery systems and imaging tools in live animals. Furthermore, our results demonstrate that the in vivo optical imaging method is helpful for in vivo sensing the biological effects of SiNPs by using luminescent dye doped in the silica matrix as a synchronous signal.

Silica urolithiasis in the dromedary camel in a subtropical climate.

In 1998, two cases of silica urolithiasis occurred in castrated male dromedaries on an intensive camel farm in the Canary Islands. The immediate attributable cause was the ingestion of large amounts of silica in the feed, estimated as 84.44 g/day. An associated cause was the low level of salt in the diet. Daily ingestion of salt from feed and water was estimated to be 21.8 g (8.6 g of sodium). Seventy-six castrated males from the same farm were divided into four groups: group A received 30 g of salt daily; group B received 40 g; group C received 60 g; and group D received no added salt in the diet (control). The animals were maintained on these dietary regimes for 2 years. No animals from groups A, B or C suffered overt urinary retention. One animal from group D had an obstructive urinary retention 10 months after the study commenced. Thus, 52 g of salt daily appears to be sufficient to prevent urinary retention in dromedaries raised in a subtropical climate.

Silica urolithiasis without magnesium trisilicate intake.

Two cases of silica stones, without previous oral intake of magnesium trisilicate, are reported. A 64-year-old Japanese woman had bilateral renal stones. Infrared spectrophotoscopy revealed that one of the fragments consisted of silicate and the others consisted of calcium oxalate. A 75-year-old woman had right renal stones. The composition of 1 stone was a mixture of silicate and unspecified matrices. Silicate urolithiasis may not necessarily be related to oral intake of silicate-containing antacids.

Minor constituents of sabulous material in equine urine.

The secondary constituents accompanying calcite and vaterite (crystalline forms of calcium carbonate) in the sabulous deposits from 140 vesical samples and one renal sample of equine urine were studied by infrared spectroscopy (IR), scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX). Apatitic calcium phosphate, present in 12 per cent of the samples, generally appeared in the form of spherulites with smooth and rough surfaces. Calcium sulphate, clearly detected by IR in 12.7 per cent of the samples, did not have a characteristic structure under SEM, although EDX detected sulphur in the samples. Amorphous silica was observed in one case and had a nodular appearance. Organic fibres were not as common as might have been expected in equine urinary deposits.

Silica stone--development due to long time oral trisilicate intake.

We report a case of a 30-year-old female who had a long-term history of trisilicate-containing antacid intake for gastric discomfort. She had experienced repeated attacks of renal colic. Neither intravenous pyelography nor ureteroscopy could define the presence of calculi. The metabolic evaluations were normal. However, X-ray diffraction revealed a silicate stone. We suggest that the attack of renal colic in those patients with long-term history of trisilicate intake should arouse the possibility of silica urolithiasis.

Diet calcium carbonate, phosphorus and acidifying and alkalizing salts as factors influencing silica urolithiasis in rats fed tetraethylorthosilicate.

Three experiments were conducted to determine the effects of excess dietary calcium carbonate, phosphorus and urine acidifying and alkalizing salts on silica urolith formation in a model using rats fed dextrose-based diets containing 2% tetraethylorthosilicate (TES). Diets containing 2% TES lowered weight gains to 91-95% of gains made by rats fed non-TES diets. Urine silica concentrations of rats fed TES were generally in the range of 50-60 mg/dl. In experiment 1, rats fed TES with no additional dietary calcium carbonate had a silica urolith incidence of 35%. With additions of 1 and 2% calcium carbonate to the basal-TES diet, respective urolith incidences were 45 and 60% (r = 0.99, P less than 0.02). In experiment 2, monobasic sodium phosphate (MP) providing 0.2% additional phosphorus resulted in a mean urine pH of 6.42 and no uroliths. Dibasic sodium phosphate (DP) without and with 0.5% sodium bicarbonate (SB) resulted in respective urine pH values of 6.78 and 7.14 and urolith incidences of 15 and 20% (MP less than DP and DP + SB, P less than 0.05). However, the uroliths were small averaging less than 1 mg. In experiment 3, substitution of autoclaved egg albumin for casein, the protein source in experiments 1 and 2, resulted in urine pH of 7.45 and a silica urolith incidence of 46%. An equal-molar mixture of MP and DP providing an added 0.2% phosphorus resulted in a urine pH of 7.07 and reduced the urolith incidence to 4%, and 0.75% of dietary ammonium chloride either with or without the added 0.2% phosphorus gave urine acidification and complete protection from uroliths.(ABSTRACT TRUNCATED AT 250 WORDS)

Canine uroliths. Analysis of data derived from 813 specimens.

This article contains an analysis of data compiled from 813 specimens of canine uroliths submitted to the Urinary Stone Analysis Laboratory at University of California School of Veterinary Medicine.

Etiopathogenesis, clinical manifestations, and management of canine silica urolithiasis.

Silica uroliths were first recognized in dogs in the mid 1970s. Currently available data suggest that dietary factors may play a role in their pathogenesis. Diagnosis is facilitated by their typical jackstone appearance but must be verified by quantitative analysis. Surgery is the only feasible method of treatment.

Silica stones in humans.

Twenty cases of silica stones (including a personal one, the first case ever observed--April 1952) are reviewed. Almost all of the patients had been taking magnesium trisilicate for several years, one up to 40 years. The average age of the patients was 54 years. There were 9 males and 1 female. The patients came from the following locations, given in chronological order: Beirut, Lebanon (1952); Stockholm, Sweden (1953, 1962); Houston, Tex., USA (1958, 1961); New York, N.Y., USA (1960); Johannesburg, South Africa (1964); London, UK (1973, 1982); Osaka, Japan (1978); Madrid, Spain (1978, 1981); and Torrance, Calif., USA (1984). 14 patients passed out the stones spontaneously. In 3 patients, the stone was formed in the left kidney. Bilateral renal stones were found in 2 patients. In 2 patients, they were removed from the left ureter and in 2 patients they were found in the bladder. The size of the stones varied between 2 mm and 3 cm, the weight from 8 mg to 3.6 g. The silica stone is of a relatively low radio density. Our case is the only one in whom the level of urinary silica was determined; it was of the order of 0.006% i.e. 1 mmol/l.

[Are silicates only gravel stones?]. / Sind Silikate nur Kieselsteine?

The presence of silicon dioxide in urinary calculi usually indicates the presence of artefacts. However in isolated cases infra-red and X-ray spectroscopy and electron-ray microanalysis have clearly demonstrated the presence of silicate in crystalline urinary sediment and as a phase of urinary calculi, probably as a result of overdoses of silicon preparations. A local silicon enrichment of up to 2% is certain in phosphate phases and makes an isomorphic incorporation of SiO4 ions probable.