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.

Graphic abstract

中文翻译：

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氟化物在神秘，肾小管间质性慢性肾脏疾病中的分子和细胞毒性：系统评价

摘要

多因素起源的慢性肾脏疾病（CKDmfo），也称为不确定来源的CKD（CKDu），是一种肾小管间质疾病。CKDmfo是一种环境导致的，可预防的职业病，主要影响热带国家的男性农民。已经提出了几种致病因素，包括农用化学品，重金属，药物，微生物/蓝细菌毒素，非法酒精，微生物，脱水和氟化物。与任何假定的肾毒素，脱水，遗传或营养不良（CKDmfo的起源）均缺乏适当的科学数据收集和分析。但是，可以通过长期暴露于含有氟化物或与其他肾毒素结合的高剂量硬水的动物实验诱导该病。受CKDmfo影响的地区的水氟化物水平各不相同，从浅井中的不足0.4 mg / L（0.4 ppm）到大多数管井中的超过1.5 mg / L，这是该地区两个最常见的饮用水来源。来自天然温泉，水库和运河的地表水中氟化物和硬度的浓度要低得多，而饮用此类水的地表水中CKDmfo的发生率则要低得多。几项动物研究报告说，氟化物会加剧肾小管的氧化应激，从而导致细胞损伤。该系统评价涵盖了CKDmfo / CKDu患者中氟化物诱导的肾小管细胞损伤，化学相互作用和氧化应激的机制。尽管该疾病是由肾小管中的纳米矿物质形成以及慢性肾脏缺血引起的，氟化物可以增加肾毒性。CaPO引起的肾小管毒性氟化物和其他肾毒素，营养不良，微量营养素和抗氧化剂缺乏以及增加氧化应激的条件加剧了_4种纳米晶体和纳米管的生长。这些数据表明可以用来预防这种致命疾病的关键目标和行动方式。尽管氟化物可能起了作用，但它不可能是CKDmfo的肾小管间质肾损害的唯一原因。

图形摘要