Molecular and cellular toxicity of fluoride in mystery, tubulointerstitial chronic kidney disease: a systematic review

Abstract

Chronic kidney disease of multifactorial origin (CKDmfo), also known as CKD of uncertain origin (CKDu), is a tubulointerstitial disease. CKDmfo is an environmentally induced, preventable occupational disease that predominantly affects male farmers in tropical countries. Several causative factors have been proposed, including agrochemicals, heavy metals, medications, microbial/cyanobacterial toxins, illicit alcohol, microbes, dehydration, and fluoride. Properly conducted scientific data collections and analyses are lacking in relation to any of the postulated nephrotoxins, dehydration, genetics, or malnutrition as the genesis of CKDmfo. However, the disease can be experimentally induced in animals with chronic exposure to high-dose hard water containing fluoride or in combination with other nephrotoxins. Water fluoride levels in CKDmfo-affected regions vary, from less than 0.4 mg/L (0.4 ppm) in shallow wells to more than 1.5 mg/L in most tube wells, which are the two most-common sources of drinking water in the regions. Surface water from natural springs, reservoirs, and canals contains much lower concentrations of fluoride and hardness and those drinking such water have a significantly lower incidence of CKDmfo. Several animal studies reported that fluoride exacerbates the renal tubular oxidative stress that contributes to cell damage. This systematic review covers the mechanisms of fluoride-induced renal tubular cell damage, chemical interactions, and oxidative stress in persons with CKDmfo/CKDu. Although the disease is initiated by nanomineral formation in renal tubules together with chronic renal ischemia, fluoride can augment the nephrotoxicity. Renal tubular toxicity caused by CaPO4 nanocrystals and nanotubes is exacerbated by fluoride and other nephrotoxins, malnutrition, micronutrients and antioxidant deficiency, and conditions that increase oxidative stress. These data indicate key targets and modes of action that could be used to prevent this deadly disease. Although fluoride likely contributes, it is unlikely to be the sole cause of the tubulointerstitial renal damage of CKDmfo.