Advanced Toxicology

www.theijoem.com Vol 11, Num 2; April, 2020 85

This work is licensed under a Creative Commons Attribution- NonCommercial-ShareAlike 4.0 International License.

To review this article online, scan this QR code with your Smartphone

Original Article

Abstract

Background: For many years, several studies drew attention to the possible nephrotoxic ef- fects 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 Egyp- tian 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), g-glutamyl trans- ferase (g-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, g-GT, LDH, and KIM-1 compared with the comparison group. Among the silica- exposed group, increased urinary Si levels were positively and significantly correlated (Spear- man'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 corre- lated (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 work- ers.

Conclusion: There is associated subclinical glomerular and tubular affection among silica- exposed workers, which is related to the duration and intensity of exposure.

Keywords: Silicon dioxide; Occupational exposure; Kidney diseases; Renal insufficiency; Kidney glomerulus; Kidney tubules; Proteinuria

Demonstration of Subclinical Early Nephrotoxicity Induced by Occupational Exposure to Silica among Workers in Pottery Industry Basma Hussein Mourad1, Yasmin Adel Ashour2

1Department of Occu- pational and Envi- ronmental Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt 2Department of Clinical Pathology, Hospitals of Ministry of Health, Cairo, Egypt

Correspondence to Basma Hussein Mourad, PhD, Faculty of Medi- cine, Cairo University, Cairo, Egypt. Tel: +2-023-569-2145 E-mail: basma.hus- [email protected] Received: Dec 12, 2019 Accepted: Feb 15, 2020

Cite this article as: Mourad BH, Ashour YA. Demonstration of subclinical early nephrotoxicity induced by oc- cupational exposure to silica among workers in pottery industry. Int J Occup Environ Med 2020;11:85-94. doi: 10.34172/ijoem.2020.1886

Introduction

O ccupational exposure to crystal- line silica has long been known to cause various lung diseases, most

notably silicosis. The main route of entry of silica into the human body is through the respiratory system as dust; the expo- sure via skin or the gastrointestinal tract is negligible. The most common industries

www.theijoem.com Vol 11, Num 2; April, 202086

a r t i c l e

and occupations that have the potential for silica exposure include mining, quarrying, foundry work, glass manufacture, ceramic, pottery, and cement production.1

Silica dust was suspected to affect the human kidney over 90 years ago. The detected pathologic renal changes are similar to those induced by nephrotoxic heavy metals in the form of dose-related nephropathy that causes degenerative changes in tubular epithelium and inter- stitial inflammation, fibrous nephrosis, glomerulonephritis, and systemic vascu- litis. Additionally, it was demonstrated that silica exposed workers can experience distinct renal histologic alterations in glo- merular and proximal tubules.2,3

Various urinary biomarkers have been proved to be useful to locate defects in spe- cific parts of the nephron and can detect early renal changes resulted from expo- sure to nephrotoxins. These biomarkers include high molecular-weight protein, and albumin for evaluating glomerular integrity—low molecular weight protein for assessing tubular protein reabsorption. As a result of tubular epithelial damage and cellular lysis, both cytosolic and lysosomal enzymes are released. Evaluating the uri- nary concentrations of these enzymes can be considered a perfect non-invasive sen- sitive method to assess tubular integrity. These significant urinary renal enzymes include alkaline phosphatase (ALP) and g-glutamyltransferase (g-GT), which are found on the epithelial cells of the proxi- mal tubule; lactate dehydrogenase (LDH) is located at distal tubular cells. Referring to several recent human studies, these uri- nary biomarkers have been used to detect early subclinical renal dysfunction.3-5

Another novel urinary biomarker that has recently been shown to have more sen- sitivity and specificity in the detection of the initial preclinical renal tubular insult, is the urinary kidney injury molecule-1 (KIM-1). A meta-analysis including 11

studies (2979 patients) estimates the uri- nary KIM-1 specificity for the diagnosis of acute renal injury at 86% and sensitivity at 74%.6 KIM-1 is a type I transmembrane glycoprotein mainly expressed on the surface of T cells. It has two extracellular domains. KIM-1 expression is low in nor- mal kidneys but is significantly increased in proximal tubular cells following kidney injury. Upon kidney injury, the extracel- lular domains of KIM-1 separate from the cell surface and enter the urine through a metalloproteinase-dependent process.7 As the tubular injury appears to precede glomerular damage in the pathophysiol- ogy of renal diseases, several recent stud- ies resorted to study the urinary levels of KIM-1 as a reliable evidence for the degree of subclinical tubular affection and hence assessing the extent of preclinical nephro- toxicity.8-10

We therefore conducted this study to demonstrate the early signs of subclinical nephrotoxic effects involving renal glom- eruli and tubules among some Egyptian workers occupationally exposed to silica in pottery industry.

Materials and Methods

In this cross-sectional study, 29 occu- pationally silica-exposed subjects were recruited from non-smoking male workers in El-Fawakhir handicraft pottery area, in Greater Cairo, Egypt. A comparison group of non-smoking male population were also selected from the administrative depart- ment of Kasr Al-Ainy hospital to include 35 matching subjects with history of usual exposure to silica during their daily life but without occupational exposure.

A questionnaire was used to identify the main demographic and lifestyle character- istics of the studied subjects such as smok- ing habit, detailed occupational history and medical history with the medication intake to reveal the possible indicators of

Early Nephrotoxicity Induced by Occupational Silica Exposure

www.theijoem.com Vol 11, Num 2; April, 2020 87

nephrotoxicity among the studied popula- tion during the time of urine collection.

The whole number of the workers in this factory was 93. The exposed group included those workers in the factory who have been exposed to the manufacturing process. It is worth to mention that 64 workers were excluded before starting the study based on the pre-determined exclu- sion criteria. Workers were excluded from the study if any was a smoker, had experi- enced kidney disease or any disease likely to impair renal functions and/or parame- ters that were to be tested (creatinine, ALP, g-GT, and LDH). Others excluded from the study were those who had previous or cur- rent potential exposure to agents capable of damaging the kidney such as lead, cad- mium, and mercury or other nephrotoxi- cants such as organic solvents. The work- ers might also be excluded if they revealed a history of having consumed drugs with potential nephrotoxicity such as analgesics and anti-inflammatory agents and abuse of aminoglycoside antibiotic therapy. The comparison group subjects were selected with comparable sex, age, socioeconomic standards, and special habits of medical importance (especially in being non-smok- ers) to the exposed group after applying the previously mentioned exclusion crite- ria.

Sample Collection

A random single-voided urine sample in a closed container was collected from each participant. The container was labelled with the study number of the participant which is written on the questionnaire form to avoid any risk of mix-ups or incorrect identification of samples. Spot urine was used because urinary protein/creatinine ratio,11 as well as dividing urinary enzyme activity by the urine creatinine concentra- tion in the random sample,12 correlates with 24-hour urinary excretion and elimi- nates variations due to changing rates

of urine output and provides a measure- ment of concentration. The collected urine sample was transported in a closed box at room temperature within two hours after the collection.

Sample Analysis

Each urine sample was analyzed to assess glomerular integrity through measur- ing urinary levels of total protein (TP) using the semiautomated Technicon Bay- er RA 1000® analyzer (Ireland Techni- con Limited), and microalbumin (Malb) using Hemocue® urine albumin system (Hemocue AB, Angelhom, Sweden); proxi- mal and distal tubular structural integ- rity by determining urinary activities of g-GT and ALP, which are proximal tubule enzymes, and LDH located at distal tubular cells,13 using automated Olympus AU640® analyser (Japan Mishima Olympus Optical Company Limited); and urinary silicon lev- els using the Buck Model 210 VGP Atomic Absorption Spectrophotometer® (Bulk Scientific, Inc).3 Urine level of KIM-1 was determined using a commercially available quantitative sandwich immunoassay tech- nique (SunRed Biotechnology Company, Shanghai, China), as per manufacturers' instructions. Urinary KIM-1 level was nor- malized by dividing by urine creatinine.10

Internal Quality Control

The internal quality control sample mate-

TAKE-HOME MESSAGE

● Prolonged and intensive occupational exposure to silica could result in subclinical nephrotoxicity. It can thus be as- sociated with an increased risk of future end-stage renal disease.

● Usage of urinary biomarkers to detect signs of preclinical glomerular and tubular affection seems to be a simple and non-invasive screening tool to identify silica-exposed work- ers who carry a higher risk of future nephropathy.

B. H. Mourad, Y. A. Ashour

a r t i c l e

www.theijoem.com Vol 11, Num 2; April, 202088

a r t i c l e

rials were run together with the urine specimen from the study subjects. Values obtained for the internal quality control materials for each of the measured param- eters was accepted if it was within ±2 SD from the target value.

Ethics

Ethical approval was sought and granted by the Ethical Committee of the Occu- pational and Environmental Medicine Department, Kasr Al-Ainy Hospital, Fac- ulty of Medicine, Cairo University, Cai- ro, Egypt. Approval was taken from the Chief Executive Officer (CEO) of the fac- tory. The participants were reassured of confidentiality in the handling of informa- tion and procedures involved in this study. Informed written consent for sharing in the study was voluntarily obtained from each individual after a proper explanation of the objectives of the current study.

Statistical Analysis

Results of all measured parameters were each divided by the levels of urinary con- centration of creatinine (in g/L)11 so as to correct for variations in urinary con- centration due to hydration.14 Data gen- erated from the study were entered into MS Excel® software and then exported to SPSS® for Windows® ver 25 for statistical analysis.

Data were tabulated as median (IQR) because most of the measured parameters were not normally distributed. Differences between investigated groups (male refer- ents, male silica-exposed subjects) were assessed by Mann-Whitney U test. Corre- lation between quantitative variables was done using Spearman's rank correlation coefficient (ρ). Univariate linear regression between quantitative variables was done to test significant predictors for measured urinary proteins and enzymes among the exposed group. A p value <0.05 was con- sidered statistically significant.

Results

Table 1 shows the levels of urinary pro- teins, enzymes, KIM-1, and silicon among the studied groups. Silica-exposed male workers had significantly increased lev- els of urinary TP, Malb, ALP, g-GT, LDH, KIM-1 and Si (p<0.001 for all except Malb, p=0.03), compared to that of the compari- son subjects.

A significant positive correlation was observed between the work duration and the urinary Si level vs all other measured urinary parameters among the exposed group (Figs 1, 2; Spearman's ρ>0.60, p<0.001 for all variables). There was no significant correlation between the age and the measured urinary parameters among silica-exposed workers.

Work duration in addition to the uri- nary Si level could be considered signifi-

Table 1: Median (IQR) of studied demographic characteristics, and the levels of urinary proteins, enzymes, KIM-1 and silicon among silica-exposed and the comparison groups

Parameter Silica-exposed (n=29)

Comparison (n=35) p value

Age (yrs) 45 (25) 39 (29) 0.096

Work duration (yrs) 25 (19) 17 (21) 0.117

TP/Cr (mg/g Cr) 560.4 (1264.6) 15.4 (137.9) 0.001

Malb/Cr (mg/g Cr) 54.3 (88.7) 1.0 (25.5) 0.03

ALP/Cr (IU/g Cr) 20.0 (25.9) 2.4 (4.6) 0.001

g-GT/Cr (IU/g Cr) 235.1 (341.3) 20.5 (74.1) 0.001

LDH/Cr (IU/g Cr) 201.4 (236.6) 29.0 (28.4) 0.001

KIM-1/Cr (pg/mg Cr) 210.4 (126.6) 120.1 (100.0) 0.001

Si/Cr (mg/g Cr) 26.4 (15.0) 2.1 (3.3) 0.001 TP: Total protein, Malb: microalbumin, ALP: Alkaline phosphatase, g-GT: g-glu- tamyl transferase, LDH: Lactate dehydrogenase, KIM-1: kidney injury molecule-1, Si: Silicon, Cr: Creatinine

Early Nephrotoxicity Induced by Occupational Silica Exposure

www.theijoem.com Vol 11, Num 2; April, 2020 89

Figure 1: Scatter plots representing linear regression between all measured urinary proteins, enzymes, KIM-1 of silica-exposed workers vs their work duration

B. H. Mourad, Y. A. Ashour

a r t i c l e

www.theijoem.com Vol 11, Num 2; April, 202090

a r t i c l e

Figure 2: Scatter plots representing linear regression between all measured urinary proteins, enzymes, KIM-1 of silica-exposed workers vs their urinary silicon level

Early Nephrotoxicity Induced by Occupational Silica Exposure

www.theijoem.com Vol 11, Num 2; April, 2020 91

cant (p<0.001) predictors for the elevated urinary parameters among silica-exposed workers. There was no significant asso- ciation between workers' age and elevated urinary parameters among the workers (Table 2).

Discussion

The results of the significantly increased urinary TP, Malb, and Si among the silica- exposed workers compared to the compar- ison subjects suggested that occupational

silica exposure could result in glomerular injury and would consequently induce glomerular-type proteinuria. Normally, the glomerular capillary epithelial cells are coated with sialoprotein layer that repels and prevents the passage of serum proteins in urine. Maintenance of sialoprotein coat integrity is mainly the function of epithe- lial cells, so damage to this system could result in proteinuria.15 These findings were in line with those of other investigators who report that crystalline silica exposure results in an elevation of urinary proteins

Table 2: Univariate linear regression analysis to detect significant predictors of measured urinary proteins, enzymes and KIM-1 from the age, work duration and urinary silicon levels among silica-exposed workers

Independent variable Dependent variables Coefficient (95% CI)

Age (yrs) TP/Cr (mg/g Cr) 16.75 (-13.52 to 45.97)

Malb/Cr (mg/g Cr) 1.07 (-1.05 to 3.08)

ALP/Cr (IU/g Cr) 0.21 (-0.41 to 0.82)

g-GT/Cr (IU/g Cr) 3.15 (-4.87 to 11.43)

LDH/Cr (IU/g Cr) 2.06 (-3.41 to 8.71)

KIM-1/Cr (pg/mg Cr) 1.07 (-3.57 to 6.58)

Work duration (yrs) TP/Cr (mg/g Cr) 43.46 (33.37 to 53.56)

Malb/Cr (mg/g Cr) 2.71 (1.987 to 3.44)

ALP/Cr (IU/g Cr) 0.69 (0.54 to 0.85)

g-GT/Cr (IU/g Cr) 10.09 (7.85 to 12.32)

LDH/Cr (IU/g Cr) 7.43 (5.43 to 9.43)

KIM-1/Cr (pg/mg Cr) 5.37 (4.07 to 6.68)

Urinary Si/Cr (mg/g Cr) TP/Cr (mg/g Cr) 44.00 (22.80 to 65.21)

Malb/Cr (mg/g Cr) 3.14 (1.86 to 4.42)

ALP/Cr (IU/g Cr) 0.83 (0.55 to 1.11)

g-GT/Cr (IU/g Cr) 10.63 (5.95 to 15.31)

LDH/Cr (IU/g Cr) 8.74 (5.28 to 12.20)

KIM-1/Cr (pg/mg Cr) 6.42 (4.11 to 8.73) TP: Total protein, Malb: microalbumin, ALP: Alkaline phosphatase, g-GT: g-glutamyl transferase, LDH: Lactate dehydrogenase, KIM-1: kidney injury molecule-1, Si: Silicon, Cr: Creatinine

B. H. Mourad, Y. A. Ashour

a r t i c l e

www.theijoem.com Vol 11, Num 2; April, 202092

a r t i c l e

among silica-exposed industrial work- ers.2,3,16,17

The significant elevation of urinary ALP, g-GT, and LDH among silica-exposed group compared to their controls suggest- ed renal tubular affection and agreed with the results of previous studies that report significantly increased biomarkers for renal proximal tubular dysfunction such as urinary retinol-binding protein (RBP) and urinary N-acetyl-β-D-glucosaminidase (NAG) among silica-exposed industrial workers.2,18,19 More recent studies used the same urinary enzymes (ALP, g-GT, and LDH) to detect early signs of subclinical nephropathic tubular effect among silica- exposed workers3 and among patients with diabetes.4,5

Additionally, the novel urinary biomarker for preclinical nephrotoxic- ity (KIM-1) showed significantly elevated levels among silica-exposed subjects com- pared with their comparison group. Uri- nary KIM-1 is not normally present but is expressed on the proximal tubule api- cal membrane with renal injury. KIM-1 has proved to be an outstanding indica- tor of kidney injury, outperforming blood urea nitrogen and serum creatinine as predictors of histopathological changes in the proximal tubule in response to many pathophysiological states or toxi- cants. Studies in man indicate that tissue expression and urinary excretion of the ectodomain of KIM-1 are sensitive and specific markers for renal injury as well as predictors of outcome.20 Consequently, the observed significantly elevated levels of KIM-1 in addition to the presence of sig- nificantly increased levels of urinary sili- con detected among the studied exposed group denoted the implications of occupa- tional exposure in inducing this nephro- toxicity. The mechanisms by which silica may damage the kidney could be either through direct (ie, renal silica particles) or indirect toxicity.21 The indirect toxicity

likely occurs when the lungs, after being exposed to silica particles, start to produce macrophages to attack the particles. This process, in addition to lymph node stim- ulation, would activate the immune sys- tem and can lead to glomerulonephritis.22 More recently, some reports and studies are associating autoimmune renal diseas- es and silica exposure where autoantibod- ies against nuclear and other self-antigens deposit in and damage kidneys.23,24

The results revealed that there was a highly significant positive correlation between the duration of occupational exposure to silica and the elevated levels of the measured urinary biomarkers among silica-exposed workers. Additionally, the linear regression analysis showed that the duration of silica exposure could be consid- ered a highly significant predicting factor for the glomerular and tubular subclinical affection. Various recent studies report an increased risk for kidney diseases with the longer duration of silica exposure based upon a dose-response trend.25-27

The observed significant positive cor- relation between the urinary Si level and all other measured urinary biomarkers among silica-exposed workers supported the suggestion that occupational silica exposure might result in disruption of both the glomerular and tubular structural integrity. Also, the results of linear regres- sion analysis revealed that the urinary Si level could be considered a significant pre- dictor for the elevated urinary parameters among the exposed group. Several studies point out that the silica-exposed industri- al workers can be exposed to highly toxic fresh crystalline silica generated during the processing of pottery products, ceramics, bricks, and tiles, while the general popula- tion could be exposed to amorphous aged silica particles with low toxicity.1,3,28 A very recent interdisciplinary research relates the variable toxicity of silica particles to their surface chemistry. New physico-

Early Nephrotoxicity Induced by Occupational Silica Exposure

www.theijoem.com Vol 11, Num 2; April, 2020 93

chemical methods can finely characterize and quantify silanols at the surface of silica particles. A silanol is a functional group in silicon chemistry with the connectivity Si– O–H. Surface silanols are critical determi- nants of the interaction between silica par- ticles and biomolecules, membranes, and cell systems in animal models.29

The observed lack of a correlation between the workers' age and their uri- nary levels of biomarkers of renal affec- tion might imply that renal insult due to silica exposure is duration and intensity related, not age-related. Furthermore, it is worth to mention that among the studied silica-exposed group, there were younger workers (aged 20's) with relatively lon- ger work duration (>10 years) and higher levels of urinary biomarkers compared to older workers with relatively shorter work duration and experienced lower levels of urinary biomarkers. This finding was also encountered by another investigator who observed no correlation between age and the studied parameters of kidney function among silica-exposed subjects.30

At the end of the study, individuals found with evidence of nephrotoxicity were referred to Kasr El-Ainy hospital for further nephrologic evaluation and follow up. The industry was also advised to apply rotational schedules for staff working in areas with significant occupational silica dust exposure to minimize the risk of renal affection.

Regarding the limitations of the study, since the used biomarkers were limited to urinary ones, we cannot deduce “definite nephrotoxicity” due to the lack of blood biomarkers and biopsies. However, uri- nary biomarkers usually provide a simple and non-invasive method of assessment with reliable results to some extent. The use of urinary ALP, g-GT and LDH rep- resented accompanied changes in urine rather than being biomarkers of kidney injury. These biomarkers, although are

not definite signs of kidney injury, were used as surrogates for kidney injury in this study. Certainly, blood biomarkers and renal biopsies should have been con- sidered for more accurate assessments of nephrotoxicity.

In conclusion, this study could draw attention to the potential subclinical neph- rotoxic effects resulted from occupational exposure to silica in pottery industry. The significant elevated levels of urinary bio- markers of glomerular and tubular affec- tion among exposed workers could support the hypothesis that silica might influence the occupationally exposed population and predispose them to expected end- stage renal diseases, depending on their exposure duration and intensity.

Conflicts of Interest: None declared.

Financial Support: None.

References

1. Moehner M, Pohrt A, Gellissen J. Occupational exposure to respirable crystalline silica and chronic non-malignant renal disease: systematic review and meta-analysis. Int Arch Occup Environ Health 2017;90:555-74.

2. EL-Safty IA, GadalIah M, Shouman AE, Nessim, DE. Subclinical nephrotoxicity caused by smoking and occupational silica exposure among Egyptian indus- trial workers. Arch Med Res 2003;34:415-21.

3. Mwangi DM, Njagi LJ, Mcligeyo SO, et al. Subclinical nephrotoxicity associated with occupational silica exposure among male Kenyan industrial workers. East Afr Med J 2009;86:244-50.

4. Gatua WK, Makumi JN, Njagi EM, et al. Evaluation of urinary tubular enzymes as screening markers of renal dysfunction in patients suffering from diabe- tes mellitus. Asian J Med Sci 2011;3,84-90.

5. Sasikala T, Bitla AR, Sachan A. Urinary brush border enzymes for early diagnosis of tubular dysfunction in patients with type 2 diabetes mellitus. Int J Res Med Sci 2019;7:2015-21. doi: 10.18203/2320-6012. ijrms20192475

B. H. Mourad, Y. A. Ashour

a r t i c l e

www.theijoem.com Vol 11, Num 2; April, 202094

a r t i c l e

6. Shao X, Tian L, Xu W, et al. Diagnostic Value of Urinary Kidney Injury Molecule 1 for Acute Kidney Injury: A Meta-Analysis. PLoS ONE 2014;9:e84131.

7. Charlton JR, Portilla D, Okusa MD. A basic science view of acute kidney injury biomarkers. Nephrol Dial Transplant 2014;29:1301-11.

8. Spasojević-Dimitrijeva B, Kotur-Stevuljević J, Đukić M, et al. Serum Neutrophil Gelatinase-Associated Lipocalin and Urinary Kidney Injury Molecule-1 as Potential Biomarkers of Subclinical Nephrotoxicity After Gadolinium-Based and Iodinated-Based Con- trast Media Exposure in Pediatric Patients with Nor- mal Kidney Function. Med Sci Monit 2017;23:4299.

9. Moresco RN, Bochi GV, Stein CS, et al. Urinary kidney injury molecule-1 in renal disease. Clin Chim Acta 2018;487:15-21.

10. Nafea OE, Zakaria M, Hassan T, et al. Subclinical nephrotoxicity in patients with beta-thalassemia: role of urinary kidney injury molecule. Drug Chem Toxicol 2019;4:1-0.

11. Biradar SB, Kallaganad GS, Rangappa M, et al. Cor- relation of spot urine protein-creatinine ratio with 24-hour urinary protein in type 2 diabetes mellitus patients: A cross sectional study. J Res Med Sci 2011;16:634-9.

12. Jung K. Enzyme activities in urine. How should we express their excretion? Eur J Clin Chem Clin Biochem 1991;29:725-9.

13. da Silva Melo DA, Saciura VC, Poloni JA, et al. Evalu- ation of renal enzymuria and cellular excretion as an marker of acute nephrotoxicity due to an overdose of paracetamol in Wistar rats. Clin Chim Acta 2006;373:88-91.

14. Barratt J, Topham P. Urine proteomics: the present and future of measuring urinary protein compo- nents in disease. CMAJ 2007;177:361-8.

15. Chang RL, Deen WM, Robertson CR, Brenner BM. Permselectivity of the glomerular capillary wall: III. Restricted transport of polyanions. Kidney Int 1975;8:212-8.

16. Ibrahim KS, Ahmed SB, Amer NM. Study of kidney dysfunction in non-silicotic Egyptian workers. Int J Hyg Environ Health 2011;214:53-8.

17. Ahmed SB, Ibrahim KS, Aziz HM, Shaheen WA. Ef- fect of occupational silica exposure on kidney with emphasis on urinary amino acids as indicator for

tubular dysfunction. J Appl Sci Res 2013;9:3742-9.

18. Boujemaa W, Laywerys R, Bernard A. Early indica- tors of renal dysfunction in silicotic workers. Scand J Work Environ Health 1994;20:180-3.

19. Hotz P, Gonzalez-Lorenzo J, Siles E, et al. Subclinical signs of kidney dysfunction following short expo- sure to silica in the absence of silicosis. Nephron 1995;70:438-42.

20. Bonventre JV. Kidney Injury Molecule‐1 (KIM‐1): a specific and sensitive biomarker of kidney injury. Scand J of Clin Lab Invest Suppl 2008;241:78-83.

21. Steenland K, Rosenman K, Socie E, Valiante D. Silicosis and end-stage renal disease. Scand J Work Environ Health 2002;28:439-42.

22. Steenland K, Goldsmith DF. Silica exposure and au- toimmune diseases. Am J Ind Med 1995;28:603-8.

23. Coccolin F, Soares F, Mizutani R, et al. Silicosis with acute renal injury and glomerulonephritis: a case report. Eur Resp J 2017;50(Suppl 61):PA1218. doi: 10.1183/1393003.congress-2017.PA1218

24. Foster MH, Ord JR, Zhao EJ, et al. Silica exposure differentially modulates autoimmunity in lupus strains and autoantibody transgenic mice. Front Immunol 2019;10:2336.

25. Fenwick S, Main J. Increased prevalence of renal disease in silica-exposed workers. Lancet 2000;356:913-4.

26. Hogan SL, Cooper GS, Savitz DA. Association of silica exposure with anti–neutrophil cytoplasmic autoantibody small-vessel vasculitis: A population- based, case-control study. Clin J Am Soc Nephrol 2007;2:290-9.

27. Vupputuri S, Parks CG, Nylander-French LA, et al. Occupational silica exposure and chronic kidney disease. Ren Fail 2012;34:40-6.

28. Stratta P, Canavese C, Messuerotti A, et al. Silica and renal diseases: no longer a problem in the 21st century? J Nephrol 2001;14:228-47.

29. Pavan C, Delle Piane M, Gullo M, et al. The puzzling issue of silica toxicity: are silanols bridging the gaps between surface states and pathogenicity? Part Fibre Toxicol 2019;16:1-0.

30. Ghahramani N. Silica nephropathy. Int J Occup Environ Med 2010;1:108-15.

Early Nephrotoxicity Induced by Occupational Silica Exposure

Copyright of International Journal of Occupational & Environmental Medicine is the property of National Iranian Oil Company Health Organization and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.