Exploring the role of excess fluoride in chronic kidney disease: A review

Introduction

Fluorine is the 13th most abundant chemical element on earth and is naturally present as its anionic form fluoride. It is mainly in igneous rocks such as granites and volcanic rocks and in minerals like biotite, amphibole, apatite, and fluorite. Fluorides also occur in sedimentary rocks derived from fluoride-rich clays or fluoride-bearing minerals. Due to water–rock interactions in aquifers, ground water is predominantly fortified with this highly electronegative element, sometimes as high as 15%, depending on the geochemistry of the surrounding area. ^{1 –3} Fluoride in water can easily make its way to human and animal bodies through the consumption of fluoride-tainted water and through diet. Trace amounts of fluoride play a positive role in growth and well-being of teeth and bones of humans and animals, even though it is not an essential mineral to the body function. The current World Health Organization Guideline recommendation on fluoride in drinking water is 1 ppm. ⁴ Excessive amounts of this element can lead to deformation of teeth as well as bones, leading to life-threatening diseases such as dental and skeletal fluorosis. In the 1940s, considering the positive aspects of fluoride to dental health, community water supplies with lower levels of fluoride (less than 0.7 mg/L) in the United States and a few other countries were fluorinated with the anticipation of enhancing dental health of communities. ^3,5 Consequently, pressure groups against such fluoridation of community waters emerged, stressing the potential adverse effects of excess fluoride in water to humans. Their main concerns were dental and skeletal fluorosis, which are easily diagnosable and also visible. Other than fluorosis, neuropathic effects, impaired thyroid function, lower intelligence of children, slow growth of the brain function, increased rates of kidney stones, and carcinogenicity due to excess fluoride were also discussed. ^{3,5 –8,9 –11} Yet few reports on kidney and liver toxicities due to excess fluoride were also found in previous literature. ^{12 –14} Unlike many other diseases, chronic kidney disease (CKD) often has no symptoms until it is very advanced. ¹⁵ This long pause in showing symptoms of kidney damage contributes to the limited attention or unawareness on the toxic effects of fluorides to kidneys. However, in some earlier studies way back to the 1930s, one can still find reports on kidney and liver toxicities due to excess fluoride in drinking water, diet, or exposure to industrial fluoride pollutants. ^13,14,16 A broad and systematic literature survey on this topic shows that there is a significant amount of literature scattered across medical, chemical, and environmental science literature on the adverse effects of fluoride to the function and the health of human and animal kidneys. The article titled Fluoridation of Drinking Water and Chronic Kidney Disease: Absence of Evidence is Not the Evidence of Absence ¹² published in 2008 explains the limitations to further investigations due to the lack of sufficient research work on this problem.

Early studies

In 1937, Roholm published a book titled “Fluorine Intoxication” after intensive research and surveys on fluoride toxicity on humans and animals. ¹³ He claimed that different animals reacted to fluoride differently, referring to his limited animal experiments. In his two postmortem examination of the kidneys of two persons who were exposed to fluoride by cryolite intoxication, he observed proliferation of interstitial tissue in one and some stagnation of fluids (stasis) found in the other. However, his conclusion was “in human cryolite intoxication renal lesion was doubtful, or probably absent.” ¹³ Contrary to Roholms’ conclusion, in the same year, another study on fluorosis in India reported that “patients show cachexia, loss of appetite and general emaciation and death usually occurring from intercurrent disease.” Further, their kidney functions were impaired in most of the cases. ¹⁴ After these early studies, a fair amount of investigations on fluoride toxicity on animals such as rats, mice, rabbits, pigs, cattle, chicken, and squirrel monkeys ^{13,16 –59} and a limited number on humans ^{6,16,19,59 –82} have been conducted.

Animal studies

Table 1 gives a summary that covers research conducted over the last nine decades (1930s to 2018) on the toxicity studies of fluoride on animal kidneys. Fluoride sensitivity of cells from different organs of rats showed that kidney cells being the most sensitive type. ¹⁷ In agreement with above finding, all reports cited in Table 1 show with certainty that there are toxic effects of excess fluorides on animal kidneys, leading to damage and dysfunction of kidneys. Further, a relationship was recognized between fluoride doses and kidney injury. ^{13,18 –59} After the pineal gland, the kidney is the most exposed to high concentrations of fluoride compared to all other soft tissues. Therefore, exposure to higher concentrations of fluoride may contribute to kidney disease. ¹¹ Fluoride is removed from the kidneys by glomerular filtration, and nearly one-third of ingested fluoride discharged in the urine within 24 h. ⁸³ Of above studies, ^{13,16,17,18,19} a considerable number of investigations specifically pointed out that there is an immediate effect of excess fluoride on tubular area of the kidney. ^{16,19 –28,36,39,40,53} Fluoride inhibits tubular reabsorption primarily in the medullary portion of the ascending limb of Henle’s loop, and this was proven by examination of renal tubular site of action of fluoride, using clearance techniques on Fischer 344 rats. ²³

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Table 1.

Toxic effects of fluoride on animal kidneys.

	Experiment	Observation/Conclusion	Reference
1	Fed fluorinated compounds with food to rats, pigs, dogs, and cows	In rats’, pigs’, and dogs’ kidney, damage observed	13
2	Fluoride sensitivity of cells from different organs from rats was tested	Kidney cells being the most sensitive type	17
3	Fed 100 and 375 ppm of NaF to rabbits and growing albino rats	Serious damage to the kidneys observed	18
4	Fed NaF in drinking water to old rats	Renal tubule hypertrophy and hyperplasia were found	19
5	Young albino rabbits injected daily with 5, 10, 20, and 50 mg/kg NaF body weight for 15 weeks	At higher doses, degeneration of kidneys including tubular epithelia was observed	20
6	Fed 10–100 ppm NaF to 100 adult male albino mice for months	Cloudy swelling and necrosis of the tubular cells and atrophy of the glomeruli, and areas of interstitial infiltration of round cells observed	21
7	First and second generation of rats exposed to 30 mg/L NaF throughout the gestation and the lactation periods	Tubular degeneration on kidneys observed	22
8	The renal tubular site of action of fluoride examined in Fischer 344 rats using clearance techniques	The results suggested that NaF and methoxyflurane alter renal function primarily by inhibiting active chloride transport in the ascending limb of Henle’s loop	23
9	Examined the effect of NaF on intracellular calcium mobilization in a normal rat kidney epithelial cell line (NRK-52E cells)	Fluorides increase the secretion of parathyroid hormone leading to calcification of renal cortical thick ascending loop of Henle and distal tubule	24
10	NaF administered intravenously as a 2% aqueous solution in the young rats (75 days old)	Single doses of NaF (20 and 30 mg/kg,) produced a mild necrosis of the tubular epithelium in the inner third of the cortex	25
11	Wistar rats acutely exposed to fluoride at a plasma concentration of 0625 μg/mL	Acute exposures to low concentrations of NaF induced a significant tubular dysfunction, resulting in diluted urine, impaired protein reabsorption, and increased calcium and phosphate urinary excretion	26
12	Apoptosis of renal tubular cells induced by NaF at different levels	The results suggested that NaF induces the apoptosis in renal tubules via activation of the Bax expression and Bcl-2 suppression	27
13	The effects of chronic fluoride excess in the mouse were studied by means of polarizing microscopy in combination with a special staining technique employing Sirius red F3B, a dye which renders collagen fibrils sharply visible	Changes occur in the interstitium, the intrinsic vasculature, and Bowman’s capsule	28
14	In vivo experiments were carried out to test the toxicity of fluoride on various enzymes isolated from different organs of rats, mice, and dogs	Lactate dehydrogenase (mice), isocitrate dehydrogenase (mice), glutathione peroxidase (rats), superoxide dismutase (rats), aspartate transaminase (rats, mice), alanine transaminase (rats, mice), alkaline phosphatase (rats), acid phosphatase (rats, mice), glucose-6-phosphatase (rats), and adenosine triphosphatase (dogs) are considerably deactivated by the fluoride ion, sometimes as higher as 90% deactivation	29
15	Administered NaF (50 mg/kg) to rats	Changes in urinary ion excretion and related enzyme activities (renal Na+ K+-ATPase activity) were observed; mitochondrial ATPase in the kidney was found to be decreased by the dose of fluoride tested	30
16	The mean kidney enzyme activity rate was measured after treating animals with fluoride	Marked reduction in kidney enzyme activity was noted in the 1 ppm group; it was measured at 0.2016 showing 47.8% decrease over the normal	31
17	Rats were treated with 5 ppm fluoride in drinking water	Significant change in the activity of succinate dehydrogenase in the kidneys of the animals maintained on higher levels of fluoride in the drinking water	32
18	Substrate inhibition of rat liver and kidney arginase with fluoride was tested	Fluoride caused substrate inhibition of kidney arginase at l-arginine concentrations above 1 mM	33
19	Rats were treated with NaF for a long-term with different concentrations in drinking water	Rats treated for 180 days showed fat deposition in the livers and the kidneys	34
20	Introduced monofluorophosphate to growing rats	Chronic toxicity to kidneys was similar to that of NaF	35
21	Chronic administration of aluminum fluoride or NaF to rats in drinking water	In the kidney, glomerular hypercellularity and mesangial proliferation were apparent in animals from both the NaF and AlF3 treatment groups. Congruent with the glomerular changes was deposition of protein in the tubules. Kidney disorders were found in both groups	36
22	One-month old female Swiss albino mice were given 60 and 120 ppm NaF in their drinking water for 30 days	Elevated fluoride in drinking water affects mammalian neurotransmitter functions as well as antioxidant systems	37
23	Uremic rats with surgically induced renal insufficiency, received 0 µg/mL, 5 µg (0.26 mmol/L), 15 µg (0.79), or 50 µg/mL (2.63 mmol/L) of fluoride in their drinking water for 3 or 6 months	There were no clinically adverse, fluoride-induced, extra-skeletal physiological, biochemical, or genetic effects of chronic exposure to common levels of fluoride in these rats	38
24	Fed small amount of NaF to rats with chronic fluorosis	Tubular degeneration on kidneys observed	16
25	Treated 0.05% NaF to 226 white rats for 3–56 days	“Kidney changes consisted primarily in dilatation of the Henle loops in the juxtacortical area of the medulla, soon followed by a flattening of the epithelium in the convoluted tubules in the cortex and a distention of the tubules, possibly due to some kind of ‘stop’ in the Henle loops.”	39
26	Fed NaF with stock diet to rats	Dilation of the Henle loops, followed by dilation of the convoluted tubules and later by inflammation NaF fed group showed chronic kidneys damages, but another group showed recovery when NaF was withdrawn from the diet	40
27	Fed 0–100 ppm NaF in water to weanling rats	Mortality was observed. Pathogenic changes were seen only in the bones and kidney	41
28	Chronic fluoride ingestion to rats	Decrease of the rate of Ca++ transport across renal tubule ER and PMs, reduction of the amount of ER and PM Ca++ pump protein present in the kidney membranes decreased 45Ca uptake by rat kidney membranes observed	42
29	Intravenous injection of 2.86, 5.71, and 8.57 mg/kg of fluorides into male Wistar rats	Relationship was recognized between fluoride doses and kidney injury. Damaged renal tissue and renal dysfunction observed	43
30	Male Wistar albino rats were treated with 18 mg/L NaF	In kidneys, atrophied and cystic glomeruli, extensive degenerative changes in tubular epithelial cells were noticed	44
31	Fed NaF in drinking water at 5 and 25 mg/L for 12 weeks to Wistar rats	Seven-fold increase of fluoride in liver and kidney observed	45
32	Mice exposed to 15 and 150 NaF mg/L in water for 30–90 days	Severe alterations in kidney and liver architectures observed	46
33	Wistar rats of chronic fluorosis were produced by subjecting them to high doses of fluoride in drinking water for a prolonged period	Total phospholipid content significantly decreased in the kidney of the rats treated with high doses of fluoride	47
34	NaF and nitrates were administered to rats orally alone or in a combination	Pancreatic and renal dysfunction was observed, and several animals developed kidney degeneration	48
35	Thirty-six young rats were used to determine the effect of the fluoride on collagen synthesis in healing of fracture	Observed the breakdown of collagen in bone, tendon, muscle, skin, cartilage, lung, kidney, and trachea	49
36	Rats were ingested with fluorides for 3 months and, acid- and pepsin-soluble collagen concentrations of skeletal muscles were monitored	Fluoride ingestion in rats led to increased degradation and solubility of the collagen protein along with downregulation of the expression of the COL1A1 gene in the skeletal muscles	50
37	Studied toxic effect of NaF on the renal cortex of adult albino rats	Fluoride administration can induce morphological degenerative changes and impairment on renal cortex. Calcium enhanced the fluoride-induced toxicity and also failed to restore renal damage induced by NaF exposure	51
38	Assessed the effect of calcium on the toxic effect of fluoride on adult female Wistar rats, and by withdrawal of fluoride exposure	CaCO3 has a potential to prevent the toxicity of fluoride by maintaining serum fluoride at a less toxic level. The toxic effects of fluoride are reversible if its exposure is withdrawn for 2 months	52
39	Investigated the mechanisms of fluoride toxicity on an immortalized cell line from rabbits	The results suggest that the Na-K-ATPase pump is a major target for fluoride toxicity in Henle’s loop	53
40	Fed pigs with fluoride	Kidney damage observed	54
41	Fed cows with fluoride	Kidney damage observed	55
42	Fed cows with fluoride	In the kidney, focal intertubular mononuclear cell infiltration was observed even at the 79 ppm level. Besides, at 132 ppm, atrophied glomeruli with more periglomerular space were noticed	56
43	Fed sheep with fluoride	Kidney degeneration and tubular necrosis associated with glomerular inflammation observed	57
44	Fed broiler chicken with fluoride	Kidney tissues showed inflammatory cellular infiltration and shrinkage of glomeruli with widened Bowman’s spaces; kidney injuries were also observed	58
45	Fed 5 ppm fluoride in drinking water for 18 months to squirrel monkeys	Significant cytochemical changes in kidneys observed	59

NaF: sodium fluoride; CaCO₃: calcium carbonate; ER: endoplasmic reticulum; PM: plasma membrane.

Fluorides affect the functioning of many enzyme pathways, and this has been shown by in vivo experiments. Kidney enzymes such as lactate dehydrogenase (mice); isocitrate dehydrogenase (mice); glutathione peroxidase (rats), superoxide dismutase (rats); aspartate transaminase (rats and mice); alanine transaminase (rats and mice); alkaline phosphatase (rats); acid phosphatase (rats, mice); glucose-6-phosphatase (rats); and adenosine triphosphatase (dogs) isolated from mice, rats, and dogs are significantly deactivated by the fluoride ion, sometimes the deactivation as high as 90%. ²⁹ Changes in urinary ion excretion and related enzymes such as kidney arginase, renal Na⁺ K⁺-ATPase, and mitochondrial ATPase in the kidney activities due to fluoride also revealed in some studies. ^30,31 Biochemical and histochemical studies on the kidney enzymes of rats subjecting to different fluoride concentrations in drinking water reviled the decrease of activities of enzymes such as alkaline phosphatase, acid phosphatase, succinic dehydrogenase, and lactic dehydrogenase. Above alterations in enzyme activities were pronounced in proximal and distal convoluted tubules of the kidney. ³¹ In another study, rats treated with higher doses of fluoride in drinking water showed a significant change in the activity of succinate dehydrogenase enzyme in the kidneys. ³² However, there are some enzymes such as alkaline phosphatase (mice) found to be activated by fluoride ion as high as 132%. ²⁹

Fat deposition in the livers and the kidneys due to excess fluoride is also shown in one experiment. ³⁴ In addition to sodium fluoride, reports on adverse effects on the kidneys by fluorinated compounds such as methoxyflurane, monofluorophosphate, and aluminum fluoride further confirm the toxicity of fluorides on kidneys. ^23,35,36 Some experiments claimed that the withdrawal of fluoride from the diet leads to the recovery of kidneys, ⁴⁰ giving some hope to people and animal who were adversely affected by excess fluoride. It is shown that there were no clinically adverse, fluoride-induced, extra skeletal physiological, biochemical, or genetic effects of chronic exposure to common levels of fluoride in rats. ³⁸ Above discussed similar experiments with rabbits, ^18,20,53 pigs, ^13,54 cows, ^55,56 sheep, ⁵⁷ chicken, ⁵⁸ and squirrel monkeys, the only primate tested ⁵⁹ showed the same adverse effects on the kidneys due to excess fluoride, further confirming the toxicity of fluoride to the animal kidneys. Further, a recent review article published in 2016 also highlights fluoride-induced nephrotoxicity, including apoptosis, ultrastructural changes, and renal tubular injury in experimental animals. ⁶⁰

Human studies

During the last few decades, the role of kidney in the metabolism and elimination of fluoride from the body has been researched and documented to some extent. ^{6,16,19,59 –80} Consumption of optimal amount of fluoride in drinking water or diet does not increase the risk of developing CKD in humans, ⁶¹ and this has been proven using animal studies too. ⁴¹ At the same time, it is repeatedly proven that an impaired kidney negatively affects the metabolism as well as excretion of fluoride from the kidney, leading to further damage to the kidneys. ^{11,62 –64,84} Therefore, especially people with kidney disorders should avoid consumption of excess amounts of fluorides either through drinking water or other sources such as food, drugs, or toothpaste. ^62,64,83 Unfortunately, inadequate studies have been conducted on the effect of higher doses of fluoride to the human kidney function. However, there is some literature that highlights the adverse effect of excess fluoride to human kidney. Of them, three recent research articles ^{78 –80} and a review ⁸¹ have provided noteworthy findings of the role of fluoride in CKD, providing credible evidences linking consumption of excess fluoride and CKD. In one investigation, various degrees of fluoride-associated damages to the architecture of tubular epithelia, such as cell swelling and lysis, cytoplasmic vacuolation, nuclear condensation, apoptosis, and necrosis, were observed. ⁷⁸ In another investigation, a case–control study conducted in 824 school children aged 8–15 years, where drinking water was contaminated with fluoride. This study showed chronic kidney damage to be higher in the affected children, other than fluorosis and significantly higher urinary fluoride as compared to the control area children. ⁷⁹ Another cross-sectional study conducted on 239 adults (18–77 years old) by monitoring four early kidney injury biomarkers (ALB, Cys-C, KIM-1, and OPN) related to environmental fluoride exposure, indicated possible tubular dysfunction due to fluoride exposure, that might increase susceptibility to the future development of CKD. ⁸⁰ Other than above recent investigations, ^{78 –80} a number of research articles written on this subject in the past. In a review article titled Effects of Fluoride on the Kidney, written in 1974, adverse effects on the kidneys by acute fluoride exposure and functional disturbances to the kidneys in the areas of endemic fluorosis have been highlighted. ⁸³ During the last three decades, quite a few studies on this subject have been reported. ^{61 –66,68 –77} According to a report from the National Research Council (NRC) of Canada, ingestion of fluoride at 12 mg per day would increase the risk for some people to develop adverse renal effects. This conclusion was based on the studies carried out on people living in regions where there is endemic fluorosis. ⁶³ Prolonged anesthesia with fluorinated compound, methoxyflurane, could lead to renal failure and death, and the causative agent was found to be the fluoride ion, the end product of the biotransformed methoxyflurane. ^65,83 Further, nephrotoxic threshold in man is believed to be around 50 μm of fluoride. ⁶⁵ Dr John Yiamouyiannis, who was a leading authority in biological effects of fluoride, has written in his book titled Fluoride: The Aging Factor (1986), “Fluoride exposure disrupt the synthesis of collagen and leads to the breakdown of collagen in bone, tendon, muscle, skin, cartilage, lung, kidney and trachea.” ^6,66 Therefore, the breakdown of collagen in the kidneys due to excess fluoride should certainly be damaging the kidneys leading to dysfunction of kidneys, paving the way to CKD. Further, inhibition of kidney enzymes by fluoride was shown by in vitro studies using kidney enzymes extracted from animals. ^{29 –32} A number of prominent scientists including Nobel Prize winners too have warned about inhibition and poisonous activity of fluoride on the kidney and other enzymes, based on their chemical and enzymological research. ⁷⁶ Hence, functions of kidney enzymes are at a greater risk due to excess fluoride, leading to kidney dysfunction.

Research results and case reports in Table 2 further confirm above discussed toxic effects of fluoride on human kidneys

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Table 2.

Toxic effects of fluoride on human kidneys.

Adverse effects/Observations	Reference
Fluoride exposure disrupts the synthesis of collagen and leads to the breakdown of collagen in bone, tendon, muscle, skin, cartilage, lung, kidney, and trachea	6,66
Individuals with kidney disease have decreased ability to excrete fluoride in urine and are at risk of developing fluorosis even at normal recommended limit of 0.7–1.2 mg/L	16
Patients with fluorosis had damaged kidneys	19
Consumption of optimal amount of fluoride in drinking water does not increase the risk of developing CKD	61
Human kidneys concentrate fluoride as much as 50-fold from plasma to urine. Portions of the renal system may, therefore, be at higher risk of fluoride toxicity than most soft tissues	63
Inorganic fluoride exerts a direct and dose-dependent cytotoxic effect on human proximal tubular epithelial (HK-2) cells	64
Nephrotoxicity was reported in patients received methoxyflurane anesthesia for surgery. Causative agent was shown to be fluoride ion	65
Fluorides induce chronic renal failure	68
An experiment on fluoride ion toxicity in human kidney collecting duct cells has shown that the mitochondrion is a target of fluoride toxicity	69
An experiment with 210 children on toxicity due to fluoride in drinking water showed toxicity of fluorides to human kidney at 2 mg/L level	70
2 mg/L fluoride in drinking water can cause renal damage in children, and damage increases with fluoride content in water	71
There is a tendency to retain a higher percentage (80%) of the absorbed fluoride doses, in children when it is around 50% for the adults	72
There is a tendency in children living in higher fluoride prone areas to retain unhealthy amounts of fluoride in their kidneys, leading to kidney damage in their adult hood, if continue to consume water and the diet from the same sources	74
Fluoride interacts with cellular systems even at low doses, and it can induce oxidative stress and modulate intracellular redox homeostasis, lipid peroxidation, and protein carbonyl content, as well as alter gene expression and cause apoptosis. Genes modulated by fluoride include those related to the stress response, metabolic enzymes, the cell cycle, cell–cell communications, and signal transduction	74
Micro molar concentrations of fluoride inhibit the enzyme human renal acid phosphatases	75
Consuming water with over 2 ppm of fluoride may cause impairment to kidney function in children, and the degree of damage is increased as the water fluoride concentration increases	61
Since kidney damage can be caused by fluoride, there can be a vicious circle by which kidney damage causes more fluoride retention, which in turns further kidney damage	76
Urinary excretion of fluoride decreases with the reduction of renal function. Once renal function is severely impaired, the excretion of fluoride in the urine decreases and serum fluoride concentration increases	77
Fluoride-associated damages to the architecture of tubular epithelia, such as cell swelling and lysis, cytoplasmic vacuolation, nuclear condensation, apoptosis, and necrosis, were observed	78
Higher kidney damage was observed other than fluorosis and significantly higher urinary fluoride as compared to the control area children where drinking water was contaminated with fluoride	79
Possible tubular dysfunction due to environmental exposure of fluoride observed	80

CKD: chronic kidney disease.

A case report on fluoride-induced chronic renal failure shows direct evidence of fluoride toxicity to kidney function. ⁶⁷ As in the case of animal experiments, ^{13,16,17,18 –60} mostly the tubular area of the human kidneys damaged due to excess fluoride, and mitochondrion is found to be the target of fluoride toxicity. ^64,69 An experiment with 210 children on toxicity due to fluoride in drinking water revealed the indication of renal tubular damage due to fluoride. ⁷⁰ Concentrations of 2.0 mg/L fluoride in drinking water can cause renal damage in children, and damage increases with fluoride content in water. ⁷¹ Due to the development of bones during the childhood, high uptake of fluoride as well as other needy minerals taking place. In humans, fluoride intake of more than 6 mg per day can lead to retention of fluoride in the kidneys, which can lead to accumulation. ⁶⁷ Therefore, when there is excess fluoride in the water or diet, naturally more fluoride will absorb into the system, especially to the kidney. Infants have impaired ability to excrete fluoride when compared with adults. Hence, there is a tendency to retain a higher percentage (80%) of the absorbed fluoride doses in the kidneys of infants, when it is around 50% for the adults. ⁷² This has been further confirmed in 2006, by a report on fluoride toxicity on humans, in the NRC report. ⁶³ It stresses that “human kidneys concentrate fluoride as much as 50-fold from plasma to urine. Portions of the renal system may therefore be at higher risk of fluoride toxicity than most soft tissues.” ⁶³ Therefore, there is a tendency in children living in higher fluoride prone areas to retain unhealthy amounts of fluoride in their kidneys, leading to kidney damage in their adolescence or as an adult, if continue to consume water and the diet from the same sources. ⁷³ Geoff pain clearly defined the fluoride as a developmental nephrotoxin in his recent technical report citing more than 350 research publications and reports. ⁸² Since kidney damage can be caused by fluoride, there can be a vicious cycle by which kidney damage causes more fluoride retention, which in turn furthers kidney damage. When the kidneys are severely impaired, the excretion of fluoride in the urine decreases and serum fluoride concentration further increases. ⁷⁶ As symptoms of kidney disease in children are often nonspecific, there is an additional greater risk for children who are living in areas with fluoride sources. As pointed out earlier on this review, even for adults, kidney disease often shows no symptoms until it is at a very advanced stage. ¹⁵ After reviewing nearly 100 years of literature, the following adverse effects on human kidneys due to excess fluoride can be listed:

immediate effects on the tubular area of the kidneys, inhibiting the tubular reabsorption;

Conclusion

This review suggests that there is a direct link between CKD and consumption of excess amount of fluorides. Excess fluoride is toxic to human and animal kidneys, and the tubular areas of the kidneys are the most vulnerable. Excess fluoride disrupts the collagen synthesis in the body, leading to kidney and other organ damages. In addition, excess fluoride inhibits some kidney and other enzyme pathways, leading to dysfunction of kidneys and other organs. Children are vulnerable to fluoride as low as 2 ppm in drinking water, due to their ability to retain absorbed fluoride as higher as 80% in the body/kidney. Therefore, if continue to consume water from the same source, could result in the child becoming an adult with a sick kidney, prone to ending up as a CKD patient. Since a considerable amount of animal studies have already been conducted on this topic, it is an urgent need to conduct furthermore research on toxicity of excess fluoride on human kidneys, including effects on kidney enzyme pathways and the interference on collagen synthesis, to have a better understanding about the role of fluoride in CKD.