We examined the relationship between urinary fluoride concentrations and levels of markers of kidney function (urinary NAG, serum RBP, serum Urea, serum C3 serum UA and serum ?1-MG) in a cross-sectional study of endemic fluorosis in China. We found that the levels of urinary NAG and serum Urea increased significantly with the increase of urinary fluoride concentration, urinary fluoride was negatively correlated with C3 in adults. Specifically, an increment of 1 mg/L in urinary fluoride was associated with 1.583 U/L increase in urinary NAG and 0.199 mmol/L increase in serum Urea after adjusting for potential confounding factors. And higher levels of urinary fluoride were associated with an increased risk of kidney function injury.

NAG is mainly distributed in the cytoplasm of the proximal tubular cell, and there was a significant increase in NAG in urine when renal tubule injury. Because of its sensitivity and accurate prediction, NAG has been widely concerned and used in clinical nephropathy examination (Yan et al., 2019). In both the linear regression model and the binary logistic regression model, there was a significantly positive relationship between urinary NAG activity and urinary fluoride concentrations in our study, which is consistent with previous studies (Xiong et al., 2007). Thus, urinary NAG can be used for early assessment of renal injury in areas of endemic fluorosis.

Urea is a waste product of nitrogen-containing compounds, metabolized by the liver and excreted in urine. High serum Urea levels may reflect kidney dysfunction. Our study found a positive correlation between urinary fluoride concentrations and serum Urea level(? = 0.199, P < 0.001)?but a study in the United States has shown the opposite which in higher water fluoride concentrations were associated with lower serum Urea (? = ? 0.93, P = 0.007) among teenagers after linear regression models adjusted for covariates (Malin et al., 2019). The possible reason for the inconsistent results is the difference in the study population. Our study subjects were adults with an average age of 58.21 (10.87), while their study subjects were adolescents with an average age of 15.32 (0.07). The duration of fluoride exposure of these two groups is different, and the body’s ability to metabolize fluoride is also different. Another difference is that they studied the relationship between fluoride concentrations in water and serum Urea, not urinary fluoride concentration. Urinary fluoride, as a reaction of internal exposure in the body, can better reflect the real situation of fluoride exposure and metabolism.

C3 plays an important role in the progression of kidney injury in human hypertensive nephropathy (Cui et al., 2017). A complement-mediated C3 glomerulopathy with predominant C3 deposition was proved to be one of the mechanisms of membranoproliferative glomerulonephritis (Riedl et al., 2017, Sethi and Fervenza, 2011). Our study found a weakly negative correlation between urinary fluoride concentrations and serum C3 (? = ? 0.037, P < 0.001), which may be related to glomerular deposition of C3. It is necessary to further explore serum C3 as a marker of kidney injury in subsequent studies.

In contrast, urinary fluoride levels were not significantly associated with serum RBP and serum UA of markers of kidney function. Studies have shown that serum RBP and UA level is a biomarker of patients with acute or chronic kidney disease, mainly used for clinical stage of patients (Andreucci et al., 2017, Goodman, 1980, Kang, 2018). Our study population is a natural population, not patients with clinical kidney disease. The study examined the relationship between fluoride exposure and kidney damage, which is more likely to be expressed as early (subclinical) damage.

Our findings showed that age and gender modified the association between fluoride exposure and marker of kidney function. We found that the increase in urinary fluoride concentrations of 1 mg/L was associated with higher increments (? = 1.955, P < 0.001) in urinary NAG in the 46–60 years old group compared with the other two groups. Urinary fluoride levels were not significantly associated with serum ?l-MG of markers of kidney function. But the relationship between urinary fluoride and serum ?1-MG was significant in the women group, which is an interesting phenomenon and can be studied in more detail in the future. Animal studies have shown that the activity of NAG in mouse kidneys, urine and plasma was correlated with age and sex (Funakawa et al., 1987). The 46–60 years of age is the stage of menopause for most people, and their specific physiological changes may lead to higher urinary NAG, which needs to be confirmed by further studies.

Our study has several strengths. Our study shows a natural population-based study in China to examine the relationship between chronic fluoride exposure and kidney function related markers among adults, and investigate fluoride exposure and early impairment of kidney function. Our study found a very stable linear correlation between urinary fluoride concentrations and urinary NAG and serum Urea in adult after sensitivity analysis, which will provide a scientific basis for the establishment of a more accurate kidney function screening program in fluorosis areas. Our study provides a basis for further evaluation and formulation of safety guidelines for fluoride exposure.

This study had several limitations. Our study was a cross-sectional investigation and is incomplete adequacy as evidence to explain the kidney toxicity of fluoride, and more longitudinal studies are needed. In our study, known factors for kidney function injury were not all collected for covariate control, which makes our results likely to be questioned by other researchers. However, this is also the disadvantage of population research compared with animal experimental research, that is, the influencing factors caused by individual differences are difficult to be controlled artificially or fully understood by researchers. Fortunately, we did our best to collect important covariates.

5. Conclusions

In conclusion, our study suggests that long-term fluoride exposure is associated with kidney function in adults. Our study found that urinary fluoride concentrations were positively correlated with both urinary NAG and serum Urea in adult, and every 1 mg/L increment of urinary fluoride was associated with 1.583 U/L increase in urinary NAG and 0.199 mmol/L increase in serum Urea after adjusting for potential confounding factors. And urinary NAG, a sensitive and robust marker of kidney dysfunction caused by fluoride exposure, could be considered for the identification of early kidney injury. Therefore, these findings will provide a theoretical basis for countries and regions with fluorosis to establish relevant health policies.

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*Original abstract online at https://www.sciencedirect.com/science/article/pii/S0147651321008472