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

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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.

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For more than 2 decades, author and his team have been studying the issues related to water contamination, fluoride, and chronic diseases allowing to gather broader information in part through the charitable foundation: https://wimalawansa.org/community_projects. His group has been engaged in public education on prevention of water and air pollution and chronic diseases, holistic approach to prevention of diseases and malnutrition, and the provision of clean water in preventing CKDmfo.

Abbreviations

Al(OH)nFm:

Aluminum hydroxide complexes

CKDu:

Chronic kidney disease of uncertain etiology

CKDmfo:

Chronic kidney disease of multifactorial origin

GIS:

Geographic Information System

F− :

Inorganic fluoride

HF:

Hydrogen fluoride

MAL:

Maximum allowable limit

MCR:

Microalbumin/creatinine ratio

NCP:

North Central Province

PO4 :

Phosphate

ROS:

Reactive oxygen species

References

  • Abdel-Moneim AM, Said KM (2007) Acute effect of cadmium treatment on the kidney of rats: biochemical and ultrastructural studies. Pak J Biol Sci 10(20):3497–3506

    CAS  Google Scholar 

  • Agalakova NI, Gusev GP (2011) Fluoride-induced death of rat erythrocytes in vitro. Toxicol Vitro 25(8):1609–1618

    CAS  Google Scholar 

  • Agalakova AA, Gusev GP (2012a) Molecular mechanisms of cytotoxicity and apoptosis induced by inorganic fluoride. ISRN Cell Biol 2012:1–16

    Google Scholar 

  • Agalakova NI, Gusev GP (2012b) Fluoride induces oxidative stress and ATP depletion in the rat erythrocytes in vitro. Environ Toxicol Pharmacol 34(2):334–337

    CAS  Google Scholar 

  • Ahmed MK et al (2015) Human health risk assessment of heavy metals in tropical fish and shellfish collected from the river Buriganga, Bangladesh. Environ Sci Pollut Res Int 22(20):15880–15890

    CAS  Google Scholar 

  • Al Attar L et al (2012) Case study: heavy metals and fluoride contents in the materials of Syrian phosphate industry and in the vicinity of phosphogypsum piles. Environ Technol 33(1–3):143–152

    CAS  Google Scholar 

  • Amerasinghe FP, Indrajith NG (1994) Postirrigation breeding patterns of surface water mosquitoes in the Mahaweli Project, Sri Lanka, and comparisons with preceding developmental phases. J Med Entomol 31(4):516–523

    CAS  Google Scholar 

  • Anuradha CD, Kanno S, Hirano S (2001) Oxidative damage to mitochondria is a preliminary step to caspase-3 activation in fluoride-induced apoptosis in HL-60 cells. Free Radic Biol Med 31(3):367–373

    CAS  Google Scholar 

  • Bae DS et al (2001) Toxicological interactions among arsenic, cadmium, chromium, and lead in human keratinocytes. Toxicol Sci 63(1):132–142

    CAS  Google Scholar 

  • Bai C, Chen T, Cui Y, Gong T, Peng X, Cui HM (2010) Effects of high fluoride on the cell cycle and apoptosis of renal cells in chickens. Biol Trace Elem Res 138:173–180

    CAS  Google Scholar 

  • Bandara JM et al (2010) Chronic renal failure in Sri Lanka caused by elevated dietary cadmium: trojan horse of the green revolution. Toxicol Lett 198(1):33–39

    CAS  Google Scholar 

  • Bandara JM et al (2011) Pollution of River Mahaweli and farmlands under irrigation by cadmium from agricultural inputs leading to a chronic renal failure epidemic among farmers in NCP, Sri Lanka. Environ Geochem Health 33(5):439–453

    CAS  Google Scholar 

  • Barbier O, Arreola-Mendoza L, Del Razo LM (2010) Molecular mechanisms of fluoride toxicity. Chem Biol Interact 188(2):319–333

    CAS  Google Scholar 

  • Battaleb-Looie S et al (2012) Geological sources of fluoride and acceptable intake of fluoride in an endemic fluorosis area, southern Iran. Environ Geochem Health 34(5):641–650

    CAS  Google Scholar 

  • Berbasova T et al (2017) Fluoride export (FEX) proteins from fungi, plants and animals are ‘single barreled’ channels containing one functional and one vestigial ion pore. PLoS ONE 12(5):e0177096

    Google Scholar 

  • Bober J, Kwiatkowskac E, Kedzierska K, Olszewska M, Stachowska E, Ciechanowski K, Chlubek D (2006) Fluoride aggravation of oxidative stress in patients with chronic renal failure. Fluoride 39(4):302–309

    CAS  Google Scholar 

  • Bodey B et al (1999) Fas (Apo-1, CD95) receptor expression in childhood astrocytomas. Is it a marker of the major apoptotic pathway or a signaling receptor for immune escape of neoplastic cells? In Vivo 13(4):357–373

    CAS  Google Scholar 

  • Bohle A, Mackensen-Haen S, Wehrmann M (1996) Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press Res 19(3–4):191–195

    CAS  Google Scholar 

  • Boivin G et al (1986) Histomorphometric profile of bone fluorosis induced by prolonged ingestion of Vichy Saint-Yorre water Comparison with bone fluorine levels. Pathol Biol (Paris) 34(1):33–39

    CAS  Google Scholar 

  • Bosch T (1996) Nephrotoxicity and fluoride from the viewpoint of the nephrologist. Anaesthesist 45(Suppl 1):S41–S45

    CAS  Google Scholar 

  • Bridges TS et al (2010) Dredging processes and remedy effectiveness: relationship to the 4 Rs of environmental dredging. Integr Environ Assess Manag 6(4):619–630

    Google Scholar 

  • Cardenas-Gonzalez MC et al (2013) Proximal renal tubular injury in rats sub-chronically exposed to low fluoride concentrations. Toxicol Appl Pharmacol 272(3):888–894

    CAS  Google Scholar 

  • Caverzasio J, Palmer G, Bonjour JP (1998) Fluoride: mode of action. Bone 22(6):585–589

    CAS  Google Scholar 

  • Chandrajith R et al (2011a) Chronic kidney diseases of uncertain etiology (CKDue) in Sri Lanka: geographic distribution and environmental implications. Environ Geochem Health 33(3):267–278

    CAS  Google Scholar 

  • Chandrajith R et al (2011b) Dose-dependent Na and Ca in fluoride-rich drinking water–another major cause of chronic renal failure in tropical arid regions. Sci Total Environ 409(4):671–675

    CAS  Google Scholar 

  • Chen W et al (2008) Arsenic, cadmium, and lead in California cropland soils: role of phosphate and micronutrient fertilizers. J Environ Qual 37(2):689–695

    CAS  Google Scholar 

  • Chen Y et al (2011) Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO Rep 12(6):534–541

    CAS  Google Scholar 

  • Chen JF et al (2019) HSP75 inhibits TGF-beta1-induced apoptosis by targeting mitochondria in human renal proximal tubular epithelial cells. Biochem Biophys Res Commun 515(1):64–71

    CAS  Google Scholar 

  • Chiemchaisri Y, Phillips PH (1963) Effect of dietary fluoride upon magnesium calcinosis syndrome. J Nutr 81:307–311

    CAS  Google Scholar 

  • Chmielewska M et al (2015) Expression of metallothioneins I and II in kidney of doxorubicin-treated rats. Exp Toxicol Pathol 67(4):297–303

    CAS  Google Scholar 

  • Chouhan S, Flora SJ (2008) Effects of fluoride on the tissue oxidative stress and apoptosis in rats: biochemical assays supported by IR spectroscopy data. Toxicology 254(1–2):61–67

    CAS  Google Scholar 

  • Christensen S et al (1985) Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats. J Clin Invest 75(6):1869–1879

    CAS  Google Scholar 

  • Dai C, Yang J, Liu Y (2003) Transforming growth factor-beta1 potentiates renal tubular epithelial cell death by a mechanism independent of Smad signaling. J Biol Chem 278(14):12537–12545

    CAS  Google Scholar 

  • Daston GP et al (1985) Toxicity of sodium fluoride to the postnatally developing rat kidney. Environ Res 37(2):461–474

    CAS  Google Scholar 

  • Davidson K et al (2005) Comparative analysis of caspase activation and apoptosis in renal tubular epithelial cells and renal cell carcinomas. Nephron Exp Nephrol 99(4):e112–e120

    CAS  Google Scholar 

  • Desalegn B et al (2011) Mycotoxin detection in urine samples from patients with chronic kidney disease of uncertain etiology in Sri Lanka. Bull Environ Contam Toxicol 87(1):6–10

    CAS  Google Scholar 

  • Dharmaratne RW (2015) Fluoride in drinking water and diet: the causative factor of chronic kidney diseases in the North Central Province of Sri Lanka. Environ Health Prev Med 20(4):237–242

    CAS  Google Scholar 

  • Dharma-Wardana MWC (2018) Chronic kidney disease of unknown etiology and the effect of multiple-ion interactions. Environ Geochem Health 40(2):705–719

    CAS  Google Scholar 

  • Dharmawardana MW et al (2014) Chronic kidney disease of unknown aetiology and ground-water ionicity: study based on Sri Lanka. Environ Geochem Health 37(2):221–231

    Google Scholar 

  • Dissanayake C (2005) Water quality in the dry Zone of Sri Lanka—some interesting health aspects. J Natl Sci Found Sri Lanka 33(3):161–168

    Google Scholar 

  • Dissanayake CB, Chandrajith R (2007) Medical geology in tropical countries with special reference to Sri Lanka. Environ Geochem Health 29(2):155–162

    CAS  Google Scholar 

  • Diyabalanage S et al (2016) Has irrigated water from Mahaweli River contributed to the kidney disease of uncertain etiology in the dry zone of Sri Lanka? Environ Geochem Health 38(3):679–690

    CAS  Google Scholar 

  • Dlugosz A, Roszkowska A, Zimmer M (2009) Oestradiol protects against the harmful effects of fluoride more by increasing thiol group levels than scavenging hydroxyl radicals. Basic Clin Pharmacol Toxicol 105(6):366–373

    CAS  Google Scholar 

  • Du C et al (2017) SOCS-1 is involved in TNF-alpha-induced mitochondrial dysfunction and apoptosis in renal tubular epithelial cells. Tissue Cell 49(5):537–544

    CAS  Google Scholar 

  • Dunuweera R, Shimomura RMG, Priyankarage M, Jayasingha P, Wimalawansa SJ (2017) Chronic kidney disease of multifunctional origin (CKDmfo) prevailing in Sri Lanka: re-evaluated. World J Pharm Res 6(16):33–36

    CAS  Google Scholar 

  • Edirisinghe E et al (2017) Geochemical and isotopic evidences from groundwater and surface water for understanding of natural contamination in chronic kidney disease of unknown etiology (CKDu) endemic zones in Sri Lanka. Isot Environ Health Stud 54:1–18

    Google Scholar 

  • Emamverdian A et al (2015) Heavy metal stress and some mechanisms of plant defense response. Sci World J 2015:756120

    Google Scholar 

  • Fina BL et al (2014) Fluoride increases superoxide production and impairs the respiratory chain in ROS 17/2.8 osteoblastic cells. PLoS ONE 9(6):e100768

    Google Scholar 

  • Gama-Axelsson T et al (2012) Serum albumin as predictor of nutritional status in patients with ESRD. Clin J Am Soc Nephrol 7(9):1446–1453

    CAS  Google Scholar 

  • Gao J et al (2014) Study on the relationship between renal apoptosis and expression of caspase protein in fluoride induced rat. Wei Sheng Yan Jiu 43(1):96–100

    CAS  Google Scholar 

  • Gao J et al (2019) Selenium attenuates apoptosis and p-AMPK expressions in fluoride-induced NRK-52E cells. Environ Sci Pollut Res Int 26(15):15685–15697

    CAS  Google Scholar 

  • Gbadebo AM (2012) Groundwater fluoride and dental fluorosis in southwestern Nigeria. Environ Geochem Health 34(5):597–604

    CAS  Google Scholar 

  • Gerster JC et al (1983) Bilateral fractures of femoral neck in patients with moderate renal failure receiving fluoride for spinal osteoporosis. Br Med J (Clin Res Ed) 287(6394):723–725

    CAS  Google Scholar 

  • Goyer RA (1989) Mechanisms of lead and cadmium nephrotoxicity. Toxicol Lett 46(1–3):153–162

    CAS  Google Scholar 

  • Greenberg SR (1986) Response of the renal supporting tissues to chronic fluoride exposure as revealed by a special technique. Urol Int 41(2):91–94

    CAS  Google Scholar 

  • Grynberg K, Ma FY, Nikolic-Paterson DJ (2017) The JNK signaling pathway in renal fibrosis. Front Physiol 8:829

    Google Scholar 

  • Gunawardena RS (1998) Demographic and socio-economic situation in a new settlement in Sri Lanka: a study of system C of the Mahaweli development programme. Sir Lanka J Popul Stud 1(1):65–84

    CAS  Google Scholar 

  • Guney M et al (2007) Protective effects of vitamins C and E against endometrial damage and oxidative stress in fluoride intoxication. Clin Exp Pharmacol Physiol 34(5–6):467–474

    CAS  Google Scholar 

  • Hauser P, Oberbauer R (2002) Tubular apoptosis in the pathophysiology of renal disease. Wien Klin Wochenschr 114(15–16):671–677

    CAS  Google Scholar 

  • He LF, Chen JG (2006) DNA damage, apoptosis and cell cycle changes induced by fluoride in rat oral mucosal cells and hepatocytes. World J Gastroenterol 12(7):1144–1148

    CAS  Google Scholar 

  • Health USDO (1974) Human Services Federal Panel on Community Water, U.S. public health service recommendation for fluoride concentration in drinking water for the prevention of dental caries. Public health reports, vol 130, no 4, p 318–331, 2015 (Washington, D.C.: 1974)

  • Health PA (1988) Financing health services in developing countries: an agenda for reform. Bull Pan Am Health Organ 22(4):416–429

    Google Scholar 

  • Higgins SP et al (2018) TGF-beta1/p53 signaling in renal fibrogenesis. Cell Signal 43:1–10

    CAS  Google Scholar 

  • Hma SH et al (2018) Arsenic, cadmium, lead, and chromium in well water, rice, and human urine in Sri Lanka in relation to chronic kidney disease of unknown etiology. J Water Health 16(2):212–222

    Google Scholar 

  • Hou W et al (2018) Cyclophilin D promotes tubular cell damage and the development of interstitial fibrosis in the obstructed kidney. Clin Exp Pharmacol Physiol 45(3):250–260

    CAS  Google Scholar 

  • Ileperuma OA, Dharmagunawardhane HA, Herath KPRP (2009) Dissolution of aluminium from sub-standard utensils under high fluoride stress: a possible risk factor for chronic renal failure in the North-Central Province. J Natl Sci Found Sri Lanka 37(3):219–222

    CAS  Google Scholar 

  • Jaishankar M et al (2014) Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol 7(2):60–72

    Google Scholar 

  • Jayasekara JM et al (2013) Geographical distribution of chronic kidney disease of unknown origin in North Central Region of Sri Lanka. Ceylon Med J 58(1):6–10

    CAS  Google Scholar 

  • Jayasekera J, Dissnayake DM, Ratnayake P, Wikramasinghe W, Radella YA, Palugaswewa WB (2012) The effects from concenrated water on reservoirs of high prevelance areas on CKD of unknonw origin in Sri Lanka on mice (Abst.). http://issuu.com/slmanews/docs/ckdu_abstract_book

  • Jayasumana C, Gunatilake S, Senanayake P (2014) Glyphosate, hard water and nephrotoxic metals: are they the culprits behind the epidemic of chronic kidney disease of unknown etiology in Sri Lanka? Int J Environ Res Public Health 11(2):2125–2147

    Google Scholar 

  • Jayathilaka N, Mendis S, Mehta FR, Dissanayake LJ, Janakan N (2013) WHO-CKDu-final report: WHO Sri Lanka CKDu report: chronic kidney disease of unknown aetiology (CKDu): a new threat to health. http://dh-web.org/place.names/posts/index.html#ckdu

  • Jayatilake N et al (2013) Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a developing country. BMC Nephrol 14(1):180

    Google Scholar 

  • Juncos LI, Donadio JV Jr (1972) Renal failure and fluorosis. JAMA 222(7):783–785

    CAS  Google Scholar 

  • Koneshan S, Rasaiah JC, Lynden-Bell RM, Lee SH (1998) Solvent structure, dynamics, and ion mobility in aqueous solution at 25 C. J Phys Chem B 102:4193–4204

    CAS  Google Scholar 

  • Krasnici N et al (2013) Distribution of selected essential (Co, Cu, Fe, Mn, Mo, Se, and Zn) and nonessential (Cd, Pb) trace elements among protein fractions from hepatic cytosol of European chub (Squalius cephalus L.). Environ Sci Pollut Res Int 20(4):2340–2351

    CAS  Google Scholar 

  • Kumar M et al (2007) Ochratoxin A and citrinin nephrotoxicity in New Zealand white rabbits: an ultrastructural assessment. Mycopathologia 163(1):21–30

    CAS  Google Scholar 

  • Kumaresan J, Seneviratne R (2017) Beginning of a journey: unraveling the mystery of chronic kidney disease of unknown aetiology (CKDu) in Sri Lanka. Glob Health 13(1):43

    Google Scholar 

  • Lar UA, Agene JI, Umar AI (2015) Geophagic clay materials from Nigeria: a potential source of heavy metals and human health implications in mostly women and children who practice it. Environ Geochem Health 37(2):363–375

    CAS  Google Scholar 

  • Levine R, Hirayama B, Wright EM (1984) Sensitivity of renal brush-border Na + -cotransport systems to anions. Biochim Biophys Acta 769(2):508–510

    CAS  Google Scholar 

  • Li L (2003) The biochemistry and physiology of metallic fluoride: action, mechanism, and implications. Crit Rev Oral Biol Med 14(2):100–114

    Google Scholar 

  • Li S et al (2013) Eukaryotic resistance to fluoride toxicity mediated by a widespread family of fluoride export proteins. Proc Natl Acad Sci USA 110(47):19018–19023

    CAS  Google Scholar 

  • Li Y et al (2018) Accumulation, interaction and fractionation of fluoride and cadmium in sierozem and oilseed rape (Brassica napus L.) in northwest China. Plant Physiol Biochem 127:457–468

    CAS  Google Scholar 

  • Lim AI et al (2014) BMP-7 represses albumin-induced chemokine synthesis in kidney tubular epithelial cells through destabilization of NF-kappaB-inducing kinase. Immunol Cell Biol 92(5):427–435

    CAS  Google Scholar 

  • Liu YJ et al (2011) Increased level of apoptosis in rat brains and SH-SY5Y cells exposed to excessive fluoride–a mechanism connected with activating JNK phosphorylation. Toxicol Lett 204(2–3):183–189

    CAS  Google Scholar 

  • Madero M, Garcia-Arroyo FE, Sanchez-Lozada LG (2017) Pathophysiologic insight into MesoAmerican nephropathy. Curr Opin Nephrol Hypertens 26(4):296–302

    CAS  Google Scholar 

  • Manocha SL, Warner H, Olkowski ZL (1975) Cytochemical response of kidney, liver and nervous system of fluoride ions in drinking water. Histochem J 7(4):343–355

    CAS  Google Scholar 

  • Mason EE, Rathmell JC (2011) Cell metabolism: an essential link between cell growth and apoptosis. Biochem Biophys Acta 1813(4):645–654

    CAS  Google Scholar 

  • Mebratu Y, Tesfaigzi Y (2009) How ERK1/2 activation controls cell proliferation and cell death: is subcellular localization the answer? Cell Cycle 8(8):1168–1175

    CAS  Google Scholar 

  • Melila M et al (2019) Cardiovascular dysfunction and oxidative stress following human contamination by fluoride along with environmental xenobiotics (Cd & Pb) in the phosphate treatment area of Togo, West Africa. J Trace Elem Med Biol 56:13–20

    CAS  Google Scholar 

  • Merkwirth C, Langer T (2009) Prohibitin function within mitochondria: essential roles for cell proliferation and cristae morphogenesis. Biochim Biophys Acta 1793(1):27–32

    CAS  Google Scholar 

  • Moher D et al (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1

    Google Scholar 

  • Murao H et al (2000) Sodium fluoride increases intracellular calcium in rat renal epithelial cell line NRK-52E. Biol Pharm Bull 23(5):581–584

    CAS  Google Scholar 

  • Nanayakkara S et al (2014) An integrative study of the genetic, social and environmental determinants of chronic kidney disease characterized by tubulointerstitial damages in the North Central Region of Sri Lanka. J Occup Health 56(1):28–38

    CAS  Google Scholar 

  • Nanayakkara S et al (2019) Systematic evaluation of exposure to trace elements and minerals in patients with chronic kidney disease of uncertain etiology (CKDu) in Sri Lanka. J Trace Elem Med Biol 54:206–213

    CAS  Google Scholar 

  • Nijtmans LG et al (2000) Prohibitins act as a membrane-bound chaperone for the stabilization of mitochondrial proteins. EMBO J 19(11):2444–2451

    CAS  Google Scholar 

  • Nobel AP, Manthrithilake H, Arasalingam S (2014) Review of literature on chronic kidney disease of unknown etiology (CKDu) in Sri Lanka. Int Water Manag Inst, Colombo

    Google Scholar 

  • Noel C et al (1985) Risk of bone disease as a result of fluoride intake in chronic renal insufficiency. Nephrologie 6(4):181–185

    CAS  Google Scholar 

  • Panov VG et al (2015) Further development of mathematical description for combined toxicity: a case study of lead-fluoride combination. Toxicol Rep 2:297–307

    CAS  Google Scholar 

  • Parekh AK, Barton MB (2010) The challenge of multiple comorbidity for the US health care system. JAMA 303(13):1303–1304

    CAS  Google Scholar 

  • Park B et al (2013) Activation of G proteins by aluminum fluoride enhances RANKL-mediated osteoclastogenesis. Korean J Physiol Pharm Off J Korean Physiol Soc Korean Soc Pharmacol 17(5):427–433

    CAS  Google Scholar 

  • Peiris-John RJ et al (2006) Exposure to acetylcholinesterase-inhibiting pesticides and chronic renal failure. Ceylon Med J 51(1):42–43

    CAS  Google Scholar 

  • Peng W et al (2019) Vitamin C attenuates sodium fluoride-induced mitochondrial oxidative stress and apoptosis via Sirt1-SOD2 pathway in F9 cells. Biol Trace Elem Res 191(1):189–198

    CAS  Google Scholar 

  • Quadri JA et al (2018) Fluoride-associated ultrastructural changes and apoptosis in human renal tubule: a pilot study. Hum Exp Toxicol 37(11):1199–1206

    CAS  Google Scholar 

  • Rai KK, Rai N, Rai SP (2018) Salicylic acid and nitric oxide alleviate high temperature induced oxidative damage in Lablab purpureus L plants by regulating bio-physical processes and DNA methylation. Plant Physiol Biochem 128:72–88

    CAS  Google Scholar 

  • Rango T et al (2015) Nephrotoxic contaminants in drinking water and urine, and chronic kidney disease in rural Sri Lanka. Sci Total Environ 518–519:574–585

    Google Scholar 

  • Reddy DV, Nagabhushanam P, Sukhija BS, Reddy AGS, Smedley PL (2010) Fluoride dynamics in the granitic aquifer of the Wailapally watershed, Nalgonda District India. Chem Geol 269:278–289

    CAS  Google Scholar 

  • Redmon JH et al (2014) Additional perspectives on chronic kidney disease of unknown aetiology (CKDu) in Sri Lanka—lessons learned from the WHO CKDu population prevalence study. BMC Nephrol 15:125

    Google Scholar 

  • Ribeiro DA et al (2017) Fluoride induces apoptosis in mammalian cells: in vitro and in vivo studies. Anticancer Res 37(9):4767–4777

    CAS  Google Scholar 

  • Ristic S et al (2012) High prevalence of risk factors for chronic kidney disease in Balkan endemic nephropathy foci. Ren Fail 34(4):467–471

    Google Scholar 

  • Roman RJ et al (1977) Renal tubular site of action of fluoride in Fischer 344 rats. Anesthesiology 46(4):260–264

    CAS  Google Scholar 

  • Rush GF, Willis LR (1982) Renal tubular effects of sodium fluoride. J Pharmacol Exp Ther 223(2):275–279

    CAS  Google Scholar 

  • Salas P et al (2013) Growth retardation in children with kidney disease. Int J Endocrinol 2013:970946

    Google Scholar 

  • Saxena I, Shekhawat GS (2013) Nitric oxide (NO) in alleviation of heavy metal induced phytotoxicity and its role in protein nitration. Nitric Oxide 32:13–20

    CAS  Google Scholar 

  • Schanz M et al (2017) Renal effects of metallothionein induction by zinc in vitro and in vivo. BMC Nephrol 18(1):91

    Google Scholar 

  • Shamseer L et al (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 350:g7647

    Google Scholar 

  • Shuhua X et al (2012) A role of fluoride on free radical generation and oxidative stress in BV-2 microglia cells. Mediators Inflamm 2012:102954

    Google Scholar 

  • Smedley PL, Nicolli HB, Macdonald DMJ, Barros AJ, Tullio JO (2002) Hydrogeochemistry of arsenic and other inorganic constituents in groundwaters from La Pampa, Argentina. Appl Geochem 17:259–284

    CAS  Google Scholar 

  • Song C et al (2017) Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway. Sci Rep 7(1):672

    Google Scholar 

  • Spak CJ, Berg U, Ekstrand J (1985) Renal clearance of fluoride in children and adolescents. Pediatrics 75(3):575–579

    CAS  Google Scholar 

  • Stauffer RE (1980) Molybdenum blue applied to arsenic and phosphorus determinations in fluoride- and silica-rich geothermal waters. Environ Sci Technol 14(12):1475–1481

    CAS  Google Scholar 

  • Stefanovic V, Polenakovic MH (1991) Balkan nephropathy. Kidney disease beyond the Balkans? Am J Nephrol 11(1):1–11

    CAS  Google Scholar 

  • Sun L et al (2014) Effect of high fluoride and high fat on serum lipid levels and oxidative stress in rabbits. Environ Toxicol Pharmacol 38(3):1000–1006

    CAS  Google Scholar 

  • Tanaka M, Hoshino Y, Nakamoto D (2019) Preliminary investigation of aluminium fluoride complexes in aqueous solutions with CE/ESI-MS and CE/ICP-MS. Rapid Commun Mass Spectrom

  • Tchounwou PB et al (2012a) Heavy metal toxicity and the environment. Exp Suppl 2012(101):133–164

    Google Scholar 

  • Tchounwou PB et al (2012b) Heavy metals toxicity and the environment. EXS 101:133–164

    Google Scholar 

  • Teegarden D et al (1995) Peak bone mass in young women. J Bone Miner Res 10(5):711–715

    CAS  Google Scholar 

  • Thrane EV et al (2001) Fluoride-induced apoptosis in epithelial lung cells involves activation of MAP kinases p38 and possibly JNK. Toxicol Sci 61(1):83–91

    CAS  Google Scholar 

  • Tinetti ME, Fried TR, Boyd CM (2012) Designing health care for the most common chronic condition—multimorbidity. JAMA 307(23):2493–2494

    CAS  Google Scholar 

  • Townsend GS, Bache BW (1992) Kinetics of aluminium fluoride complexation in single- and mixed-ligand systems. Talanta 39(11):1531–1535

    CAS  Google Scholar 

  • Tseng AH, Shieh SS, Wang DL (2013) SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med 63:222–234

    CAS  Google Scholar 

  • van de Water B, Nagelkerke JF, Stevens JL (1999) Dephosphorylation of focal adhesion kinase (FAK) and loss of focal contacts precede caspase-mediated cleavage of FAK during apoptosis in renal epithelial cells. J Biol Chem 274(19):13328–13337

    Google Scholar 

  • van de Water B et al (2001) Suppression of chemically induced apoptosis but not necrosis of renal proximal tubular epithelial (LLC-PK1) cells by focal adhesion kinase (FAK). Role of FAK in maintaining focal adhesion organization after acute renal cell injury. J Biol Chem 276(39):36183–36193

    Google Scholar 

  • Verta M et al (2009) A decision framework for possible remediation of contaminated sediments in the River Kymijoki, Finland. Environ Sci Pollut Res Int 16(1):95–105

    CAS  Google Scholar 

  • Verzola D et al (2004) Testosterone promotes apoptotic damage in human renal tubular cells. Kidney Int 65(4):1252–1261

    CAS  Google Scholar 

  • Vinals F et al (1997) Effect of cations on the tyrosine kinase activity of the insulin receptor: inhibition by fluoride is magnesium dependent. Mol Cell Biochem 171(1–2):69–73

    CAS  Google Scholar 

  • Wang AG et al (2004) Effects of fluoride on lipid peroxidation, DNA damage and apoptosis in human embryo hepatocytes. Biomed Environ Sci 17(2):217–222

    Google Scholar 

  • Wanigasuriya K (2012) Aetiological factors of chronic kidney disease in the north central province of Sri Lanka: a review of evidence to-date. J College Commun Phys Sri Lanka 17(1):15–20

    Google Scholar 

  • Wanigasuriya KP et al (2007) Chronic renal failure in North Central Province of Sri Lanka: an environmentally induced disease. Trans R Soc Trop Med Hyg 101(10):1013–1017

    Google Scholar 

  • Wanigasuriya KP et al (2008) Could ochratoxin A in food commodities be the cause of chronic kidney disease in Sri Lanka? Trans R Soc Trop Med Hyg 102(7):726–728

    Google Scholar 

  • Wanigasuriya KP, Peiris-John RJ, Wickremasinghe R (2011) Chronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause? BMC Nephrol 12:32

    Google Scholar 

  • Warnakulasuriya KA et al (1992) Determining optimal levels of fluoride in drinking water for hot, dry climates–a case study in Sri Lanka. Community Dent Oral Epidemiol 20(6):364–367

    CAS  Google Scholar 

  • Wasana HM et al (2016) Drinking water quality and chronic kidney disease of unknown etiology (CKDu): synergic effects of fluoride, cadmium and hardness of water. Environ Geochem Health 38(1):157–168

    CAS  Google Scholar 

  • Wasana HM et al (2017) WHO water quality standards Vs Synergic effect(s) of fluoride, heavy metals and hardness in drinking water on kidney tissues. Sci Rep 7:42516

    CAS  Google Scholar 

  • Waugh DT (2019) Fluoride exposure induces inhibition of sodium-and potassium-activated adenosine triphosphatase (Na(+), K(+)-ATPase) enzyme activity: molecular mechanisms and implications for public health. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph16081427

    Article  Google Scholar 

  • Weaver VM, Fadrowski JJ, Jaar BG (2015) Global dimensions of chronic kidney disease of unknown etiology (CKDu): a modern era environmental and/or occupational nephropathy? BMC Nephrol 16:145

    Google Scholar 

  • Weeraratne S, Wimalawansa SJ (2015) A major irrigation project (Accelerated Mahaweli Programme) and the chronic kidney disease of multifactorial origin in Sri Lanka. Int J Environ Agric Res 1(6):16–27

    Google Scholar 

  • Wei Q et al (2018) The mitochondrial pathway is involved in sodium fluoride (NaF)-induced renal apoptosis in mice. Toxicol Res (Camb) 7(5):792–808

    CAS  Google Scholar 

  • Welch V et al (2012) PRISMA-Equity 2012 extension: reporting guidelines for systematic reviews with a focus on health equity. PLoS Med 9(10):e1001333

    Google Scholar 

  • Whitford G (1996) The metabolism and toxicity of fluoride, 2nd edn. Karger, Basel

    Google Scholar 

  • Whitford GM, Pashley DH, Stringer GI (1976) Fluoride renal clearance: a pH-dependent event. Am J Physiol 230(2):527–532

    CAS  Google Scholar 

  • Wickremasinghe AR, Peiris-John RJ, Wanigasuriya KP (2011) Chronic kidney disease of unknown aetiology in the North Central Province of Sri Lanka: trying to unravel the mystery. Ceylon Med J 56(4):143–146

    CAS  Google Scholar 

  • Wijeratne C, Weragoa SK, Kawakami T (2014) Review of chronic kidney disease due to unknown etiology and groundwater quality in dry zone in Sri Lanka. J Environ Eng 1(4):53–57

    Google Scholar 

  • Wijetunge S et al (2015) Endemic chronic kidney disease of unknown etiology in Sri Lanka: correlation of pathology with clinical stages. Indian J Nephrol 25(5):274–280

    CAS  Google Scholar 

  • Wimalawansa SJ (2013a) Chronic kidney disease in Rajarata, worse than tsunami, in Sunday observer. Colombo. http://www.sundayobserver.lk/2013/11/24/fea06.asp. Accessed 7 July 2019

  • Wimalawansa SJ (2013b) Olcott oration-2013: https://wimalawansa.org/sites/all/files/Olcott_Oration_2013_b.pdf. Accessed 7 July 2019

  • Wimalawansa SJ (2014a) Escalating chronic kidney diseases of multi-factorial origin in Sri Lanka: causes, solutions, and recommendations. Environ Health Prev Med 19(6):375–394

    Google Scholar 

  • Wimalawansa SJ (2014b) Prevention of CKD of multi-factorial origin (CKD-mfo): issues, gravity, & the importance of early diagnosis. In: 5th International conference on sustainable built environment; “environment pollution of prevention of CKD-mfo in Sri Lanka”, 2014. ICSBE, Kandy, Sri Lanka

  • Wimalawansa SJ (2015a) Agrochemicals and chronic kidney disease of multifactorial origin: environmentally induced occupational exposure disease. Int J Nephrol Kidney Fail 1(2):1–9

    Google Scholar 

  • Wimalawansa SJ (2015b) Escalating chronic kidney diseases of multi-factorial origin (CKD-mfo) in Sri Lanka: causes, solutions, and recommendations-update and responses. Environ Health Prev Med 20(2):152–157

    Google Scholar 

  • Wimalawansa SJ (2015c) Escalating Chronic Kidney Diseases in Sri Lanka: causes, solutions and recommendations—update and responses. Environ Health Prev Med 20:152–157

    Google Scholar 

  • Wimalawansa SJ (2015d) Strategic framework for managing non communicable diseases: preventing chronic kidney disease of multifactorial origin (CKDmfo/CKDu) as an example. Chronic Dis Int 2(2):1–9

    Google Scholar 

  • Wimalawansa SJ (2016a) The role of ions, heavy metals, fluoride, and agrochemicals: critical evaluation of potential aetiological factors of chronic kidney disease of multifactorial origin (CKDmfo/CKDu) and recommendations for its eradication. Environ Geochem Health 38:639–678

    CAS  Google Scholar 

  • Wimalawansa SJ (2016b) The role of ions, heavy metals, fluoride, and agrochemicals: critical evaluation of potential aetiological factors of chronic kidney disease of multifactorial origin (CKDmfo/CKDu) and recommendations for its eradication. Environ Geochem Health 38(3):639–678

    CAS  Google Scholar 

  • Wimalawansa SJ (2019) Public health interventions for chronic diseases: cost–benefit modelizations for eradicating chronic kidney disease of multifactorial origin from tropical countries. Heliyon. (in press)

  • Wimalawansa SA, Wimalawansa SJ (2014a) Impact of changing agricultural practices on human health: chronic kidney disease of multi-factorial origin in Sri Lanka. Wudpecker J Agric Res 3(5):110–124

    Google Scholar 

  • Wimalawansa SA, Wimalawansa SJ (2014b) Agrochemical-related environmental pollution: effects on human health. Glob J Biol Agric Health Sci 3(3):72–83

    Google Scholar 

  • Wimalawansa S, Wimalawansa SJ (2014c) Water pollution associated occupational diseases: special emphasis on chronic kidney disease of multifactorial origin (CKDmfo/CKDu). Jacob J Environ Sci (submitted)

  • Wimalawansa SJ, Wimalawansa SA (2015) Chronic kidney disease of multifactorial origin (CKDmfo) in Sri Lanka: escalating incidence and long-term survival estimates. J. Nephrol Urol Res 22(4):1–17

    Google Scholar 

  • Wimalawansa S, Ileperuma O, Weeraratne S (2018) Attempts to change the globally accepted term, CKDu, to KDUCAL, NUCAL, or CINAC are inappropriate. Am J Kidney Dis 71(6):914

    Google Scholar 

  • Wittinghofer A (1997) Signaling mechanistics: aluminum fluoride for molecule of the year. Curr Biol 7(11):R682–R685

    CAS  Google Scholar 

  • Wyllie AH (2010) “Where, O death, is thy sting?” A brief review of apoptosis biology. Mol Neurobiol 42(1):4–9

    CAS  Google Scholar 

  • Xu H et al (2008) Role of oxidative stress in osteoblasts exposed to sodium fluoride. Biol Trace Elem Res 123(1–3):109–115

    CAS  Google Scholar 

  • Yang B et al (2007) 1-Methylhydantoin cytotoxicity on renal proximal tubular cells in vitro. Ren Fail 29(8):1025–1029

    CAS  Google Scholar 

  • Yang Y et al (2015) Effect of oxidative stress on fluoride-induced apoptosis in primary cultured Sertoli cells of rats. Int J Environ Health Res 25(1):1–9

    Google Scholar 

  • Ye J et al (2015) Prohibitin protects proximal tubule epithelial cells against oxidative injury through mitochondrial pathways. Free Radic Res 49(11):1393–1403

    CAS  Google Scholar 

  • Yu R et al (2002) Effects of selenium and zinc on rat renal apoptosis and change of cell cycle induced by fluoride. Zhonghua Yu Fang Yi Xue Za Zhi 36(4):219–221

    CAS  Google Scholar 

  • Yu RA et al (2006) Effects of selenium and zinc on renal oxidative stress and apoptosis induced by fluoride in rats. Biomed Environ Sci 19(6):439–444

    CAS  Google Scholar 

  • Zeng Y et al (2012) Aristolochic acid I induced autophagy extenuates cell apoptosis via ERK 1/2 pathway in renal tubular epithelial cells. PLoS ONE 7(1):e30312

    CAS  Google Scholar 

  • Zhang Y et al (2003) Effects of fluoride on cell cycle and apoptosis in cultured osteoblasts of rats. Wei Sheng Yan Jiu 32(5):432–433

    CAS  Google Scholar 

  • Zhang X et al (2019) Protective effect of berberine on high glucose and hypoxia-induced apoptosis via the modulation of HIF-1alpha in renal tubular epithelial cells. Am J Transl Res 11(2):669–682

    Google Scholar 

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Acknowledgements

The author appreciates the constructive input of Professor C.B. Dissanayake on the manuscript.

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    Sunil J. Wimalawansa

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Wimalawansa, S.J. Molecular and cellular toxicity of fluoride in mystery, tubulointerstitial chronic kidney disease: a systematic review. Rev Environ Sci Biotechnol 19, 117–147 (2020). https://doi.org/10.1007/s11157-019-09521-0

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