Globally, 33187000 DALYs and 956000 deaths are attributed to chronic kidney disease (CKD) every year. Diabetes and hypertension are the two most common causes of CKD. Another category of CKD without any known common causes, chronic kidney disease of unknown etiology (CKDu) is also increasingly reported from different regions of the world such as Central America, Sri Lanka, and India. They are predominately observed in agricultural communities where crops such as sugarcane and coconut are commonly cultivated. Young adults and males are at higher risk of developing CKDu. It mainly affects individuals belonging to lower socioeconomic status. Exposure to silica, arsenic, and fluoride might be associated with increased prevalence of CKDu. The role of heat stress in contributing to CKD through dehydration is unclear but cannot be ruled out. Mycotoxins such as aflatoxins and ochratoxins are also found to be associated with CKDu in some settings. Several studies have reported that CKDu has a significant positive association with pesticides used in agriculture such as HCH, Endosulfan, Alachlor, and Pendimethalin. There is also a possible role of infections by Hantavirus and Leptospirosis in acute febrile phase of CKDu. However, there is no conclusive evidence from studies conducted on CKDu regarding its causes and risk factors. Therefore, large-scale studies with better methodology need to be conducted to study the etiology and pathogenesis of CKDu in various settings.
Globally, chronic kidney disease (CKD) is one of the leading causes of disability and deaths among all non-communicable diseases (NCDs) contributing to 33187000 disability adjusted life years (DALYs) and 956000 deaths in 2013.[1,2] CKD is defined as reduced glomerular filtration rate (GFR <60 ml/min) and/or kidney damage (structural or functional abnormalities other than GFR) for more than 3 months. Common causes and risk factors of CKD are ageing, genetic predisposition, smoking, alcohol intake, obesity, diabetes, and hypertension. Without the presence of these risk factors, CKDs have been reported from different parts of the world including Central America, Sri Lanka, and India.[5,6,7] According to KDIGO 2012 Clinical Practice Guidelines, they are known as chronic kidney disease of unknown etiology (CKDu). They are also known as chronic agricultural nephropathy (CAN) and CKD of multifactorial origin (CKD-mfo).[9,10] There are several explanations that CKDu could be due to exposure to specific diet, environmental toxins, heat stress, infections, and others. In this review, we summarized the distribution and possible determinants of CKDu throughout the world [Table 1].
|Lower socioeconomic status||?Cadmium|
|Inadequate health care delivery system||?Lead|
|Heat stress and dehydration|
In agricultural communities of El Salvador, the prevalence of CKDu was found to be 15.4% to 21.1%. In another Mesoamerican country Nicaragua, it was 12.7% based on reduced glomerular filtration rate (GFR) alone. These are predominately agricultural communities where the main crop of cultivation is sugarcane. Prevalence was found to be lesser in communities, which cultivate coffee more compared to sugarcane (6.5%). Urinary renal damage markers were used for measuring the prevalence in the above study. In Sri Lanka, the prevalence was ranging from 2.3% to 9.5%, especially in the provinces of North Central, Eastern, and Uva. There are also predominately agricultural areas where chena cultivation is popular. Chena cultivation is a primitive form of cultivation where a farmer cuts down the trees of a small area of land in the jungle, sets fire to the woody growths, and cultivates the land, moving on the next year to fresh land. The prevalence was found to be very high (61%) in the Udhanam district of Andhra Pradesh, India based on reduced GFR. In this district, the predominant crops cultivated are coconut, cashews, rice, and jack fruit. Variations in the prevalence of CKDu could be explained by the variations in their geography, cultivation, and different definitions of CKDu. Mostly adults working in agriculture for a longer duration were affected in all the communities. However, low prevalence of CKDu in older age groups suggests that pathology occurred due to recent exposure.[15,17] In almost all sites of CKDu reported, males were affected more than females.[11,12,13,16,18] However, it was slightly higher in females than males in few communities of El Savlador. Almost all the affected individuals belong to lower socioeconomic status. Most of the affected hotspots are located in countries with poor health care delivery system where there is also lack of information regarding the actual burden of chronic diseases including CKDu. Therefore, the incidence of CKDu may be much more than what is being reported. This also contributes to increased incidence of end-stage renal disease among them.
Based on the distribution of CKDu with respect to sociodemography, occupation, and geographical factors, it is hypothesized that the disease could be related to the environment. Role of heavy metals such as cadmium, arsenic, lead, and others present in water, food, and fish have been studied. Chandrajith et al. found that sodium and calcium interactions in the presence of fluoride could be associated with the increasing prevalence of CKDu in Sri Lanka. In Andhra Pradesh, India, researchers found that CKDu may be associated with high levels of silica in drinking water sources. Studies conducted in Sri Lanka and Central America found that lead levels were not elevated in CKDu patients.[15,23] In a systematic review by Zheng et al., it was found that elevated levels of arsenic in the communities were associated with CKD. It was further confirmed by reduction in renal disease mortality following the cessation of exposure to arsenic. Similarly, studies conducted by Rango et al. and Nanayakkara et al. found that there were no clear relationship between the presence of heavy metals in drinking water and CKDu.[26,27]
In hot working environment, dehydration due to heat stress can affect the renal function of the employees. Similarly, recurrent volume depletion could lead to cumulative subclinical damage of the kidney resulting in CKD. In a large nationwide cohort study conducted among 37816 workers, it was found that the odds of developing kidney disease among men exposed to prolonged heat stress was 2.22 times that of men without such exposure (95% CI, 1.48–3.35). One of the limitations of this study was that both the exposure and outcomes were self-reported. However, a study by VanDervort et al. found that there was no clear association between ambient temperature and CKDu.
Desalegn et al. conducted a study among CKDu patients of North Central Province of Sri Lanka to identify the presence of nephrotoxic mycotoxins in their urine samples. They found that 61.29%, 93.5%, and 19.4% of the CKDu patients had aflatoxins, ochratoxins, and fumonisins in their samples, respectively. They also compared the levels with their healthy relatives and healthy Japanese individuals. Patient’s mycotoxins levels were similar to their healthy relatives but higher than healthy Japanese individuals. However, a study assessing the levels of ochratoxins in food samples collected from the same North Central Province of Sri Lanka found that they were below the recommended statutory maximum limit. Therefore, the role of ochratoxins in the causation of nephropathy is doubtful.
In two rural agricultural communities of Nicaragua, population-based, cross-sectional study found that application of pesticide and chronic kidney had positive association with odds ratios of 4.80 (2.33–9.89). Similar positive associations with odds ratio of 1.38 (0.90–2.11) and 5.5 (2.8–10.7) were also found in case control studies conducted among 997 volunteers and 499 hospitalized patients, respectively, in Nicaragua. However, in all three studies, the exposure was assessed using crude methods.[33,34] In Sri Lanka, positive association (2.34 [0.97–5.57]) between CKDu and pesticide applications was found by Jayasumana et al. in a hospital-based case control study with high internal validity. In India, CKDu patients with GFR <90 ml/min/1.73 m2 with or without proteinuria for 3 months had significantly higher blood concentrations of ?–HCH, ?-HCH, total HCH, ?-endosulfan, ?-endosulfan, aldrin, p, p?-DDE, and total pesticides. The strength of association between all pesticides (third to first tertile) and CKDu was 2.73 (1.46–9.47). In USA, out of 55,580 licensed pesticide applicators followed from 1993 to 1997, 320 developed ESRD. The highest category users had significantly increased hazard ratio (HR) as compared to nonusers, and there were significant exposure–response trends for the following pesticides: Alachlor HR = 1.51 [1.08–2.13], p for trend 0.015; Atrazine HR = 1.52 [1.11–2.09], p for trend 0.008; Metolachlor HR = 1.53 [1.08–2.13], p for trend 0.008; Paraquat HR = 2.15 [1.11–4.15], p for trend 0.016; Pendimethalin HR = 2.13 [1.20–3.78], p for trend 0.006. In contrast to the above studies with positive association with pesticide exposure, there were no associations between CKDu and pesticide exposure in many other studies conducted globally.[12,38,39,40,41]
In a study conducted by Wijkstroem et al. in Sri Lanka, chronic glomerular and tubulointerstitial damage with glomerulosclerosis, glomerular hypertrophy, and mild to moderate tubulointerstitial changes were the key findings of kidney biopsies of 11 CKDu patients. There were also findings indicative of active and chronic pyelonephritis with moderate to severe interstitial inflammation, which was similar to the findings observed among 19 male sugarcane workers in Nicaragua. In a Sri Lankan study, eight out of 11 patients showed positive IgG antibodies for Hantavirus infection. Similarly in another cross-sectional study from Sri Lanka assessing the levels of Hantavirus IgG antibodies among 132 CKDu patients and 200 healthy controls, 54.5% of CKDu patients were seropositive compared to 13.5% of healthy controls. Based on the ecological and epidemiological evidence available in Central America, Murray et al. suggested that the rodent borne disease specifically leptospirosis may be the possible etiology for CKDu, particularly during the acute stage associated with febrile illness.
From the available evidence, it is suggested that CKDu may be caused by multiple factors such as geographical, agriculture, heavy metals, heat stress, mycotoxins, agrochemicals, and infections. However, the above hypothesis has not been proved significantly. Therefore, large-scale studies with better methodologies need to be conducted to study the etiology and pathogenesis of CKDu. Simultaneously, efforts should be taken by all stakeholders in a coordinated manner to prevent and control the disease based on the available knowledge.
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- Murray CJL, Barber RM, Foreman KJ, Abbasoglu Ozgoren A, Abd-Allah F, Abera SF, et al. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: Quantifying the epidemiological transition. Lancet. 2015;386:2145–91. [PMC free article] [PubMed] [Google Scholar]
- GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–71. [PMC free article] [PubMed] [Google Scholar]
- Levey AS, Levin A, Kellum JA. Definition and classification of kidney diseases. American Journal of Kidney Diseases. 2013;61(5):686–688. [PubMed] [Google Scholar]
- Kazancio?lu R. Risk factors for chronic kidney disease: An update. Kidney Int Suppl. 2013;3:368–371. [PMC free article] [PubMed] [Google Scholar]
- Ramirez-Rubio O, McClean MD, Amador JJ, Brooks DR. An epidemic of chronic kidney disease in Central America: An overview. J Epidemiol Community Health. 2013;67:1–3. [PubMed] [Google Scholar]
- Nanayakkara S, Senevirathna ST, Karunaratne U, Chandrajith R, Harada KH, Hitomi T, et al. Evidence of tubular damage in the very early stage of chronic kidney disease of uncertain etiology in the North Central Province of Sri Lanka: A cross-sectional study. Environ Health Prev Med. 2012;17:109–17. [PMC free article] [PubMed] [Google Scholar]
- Reddy DV, Gunasekar A. Chronic kidney disease in two coastal districts of Andhra Pradesh, India: Role of drinking water. Environ Geochem Health. 2013;35:439–454. [PubMed] [Google Scholar]
- Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1–50. [Google Scholar]
- Wimalawansa SJ. Escalating chronic kidney diseases of multifactorial origin in Sri Lanka: Causes, solutions, and recommendations. Environ Health Prev Med. 2014;19:375–94. [PMC free article] [PubMed] [Google Scholar]
- Jayasinghe S. Chronic kidney disease of unknown etiology should be renamed chronic agrochemical nephropathy. MEDICC Rev. 2014;16:72–4. [PubMed] [Google Scholar]
- Orantes CM, Herrera R, Almaguer M, Brizuela EG, Núñez L, Alvarado NP, et al. Epidemiological characterization of chronic kidney disease in agricultural communities in El Salvador. MEDICC Rev. 2014;15:23–30. [PubMed] [Google Scholar]
- O’Donell JK, Tobey M, Weiner DE, Stevens LA, Johnson S, Stringham P, et al. Prevalence of and risk factors for chronic kidney disease in rural Nicaragua. Nephrol Dial Transplant. 2011;26:2798–805. [PMC free article] [PubMed] [Google Scholar]
- Torres C, Aragón A, González M, López I, Jakobsson K, Elinder CG, et al. Decreased kidney function of unknown cause in Nicaragua: A community-based survey. Am J Kidney Dis. 2010;55:485–96. [PubMed] [Google Scholar]
- Athuraliya NT, Abeysekera TD, Amerasinghe PH, Kumarasiri R, Bandara P, Karunaratne U, et al. Uncertain etiologies of proteinuricchronic kidney disease in rural Sri Lanka. Kidney Int. 2011;80:1212–21. [PubMed] [Google Scholar]
- Jayatilake N, Mendis S, Maheepala P, Mehta FR. Chronic kidney disease of uncertain aetiology: Prevalence and causative factors in a developing country. BMC Nephrol. 2013;14:180. [PMC free article] [PubMed] [Google Scholar]
- Machiraju RS, Yaradi K, Gowrishankar S, Edwards KL, Attaluri S, Miller F, et al. Epidemiology of Udhanam endemic nephropathy. J Am Soc Nephrol. 2009;20:643A. [Google Scholar]
- Senevirathna L, Abeysekera T, Nanayakkara S, Chandrajith R, Ratnatunga N, Harada KH, et al. Risk factors associated with disease progression and mortality in chronic kidney disease of uncertain etiology: A cohort study in Medawachchiya, Sri Lanka. Environ Health Prev Med. 2012;17:191–8. [PMC free article] [PubMed] [Google Scholar]
- Orantes CM, Herrera R, Almaguer M, Brizuela EG, Hernández CE, Bayarre H, et al. Chronic kidney disease and associated risk factors in the Bajo Lempa Region of El Salvador. Nefrolempa study, 2009. MEDDIC Rev. 2011;13:14–22. [PubMed] [Google Scholar]
- Peraza S, Wesseling C, Aragón A, Leiva R, García RA, Torres C, et al. Decreased kidney function among agricultural workers in El Salvador. Am J Kidney Dis. 2012;59:531–40. [PubMed] [Google Scholar]
- Rajapurkar MM, John GT, Kirpalani AL, Abraham G, Agarwal SK, Almeida AF, et al. What do we know about chronic kidney disease in India: First report of the Indian CKD registry. BMC Nephrol. 2012;13:10. [PMC free article] [PubMed] [Google Scholar]
- Chandrajith R, Dissanayake CB, Ariyarathna T, Herath HM, Padmasiri JP. Dose-dependent Na and Ca in fluoride-rich drinking water-anothermajor cause of chronic renal failure in tropical arid regions. Sci Total Environ. 2011;409:671–5. [PubMed] [Google Scholar]
- Chatterjee R. Mysterious kidney disease goes global Science. 2016. [Last accessed on 2017 Nov 25]. Available from: http://wwwsciencemagorg/news/2016/03/mysterious-kidney-disease-goes-globalhttp://wwwsciencemagorg/news/2016/03/mysterious-kidney-disease-goes-global .
- McClean MD, Amador J, Laws R, Kaufman J, Weiner D, Rodr?guez J, et al. Biological sampling report: Investigating biomarkers of kidney injury and chronic kidney disease among workers in Western Nicaragua; Boston University School of Public Health. 2012. [Last accessed on 2019 Apr 26]. Available from: http://wwwcao-ombudsmanorg/cases/document-links/documents/Biological_Sampling_Report_April_2012pdf .
- Zheng L, Kuo CC, Fadrowski J, Agnew J, Weaver VM, Navas-Acien A. Arsenic and chronic kidney disease: A systematic review. Curr Environ Health Rep. 2014;1:192–207. [PMC free article] [PubMed] [Google Scholar]
- Chiu HF, Yang CY. Decreasing trend in renal disease mortality after cessation from arsenic exposure in a previous arseniasis-endemic area in southwestern Taiwan. J Toxicol Environ Health A. 2005;68:319–27. [PubMed] [Google Scholar]
- Rango T, Jeuland M, Manthrithilake H, McCornick P. Nephrotoxic contaminants in drinking water and urine, and chronic kidney disease in rural Sri Lanka. Sci Total Environ. 2015;518(519):574–85. [PubMed] [Google Scholar]
- Nanayakkara S, Senevirathna S, Abeysekera T, Chandrajith R, Ratnatunga N, Gunarathne ED, et al. 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. 2014;56:28–38. [PubMed] [Google Scholar]
- Tawatsupa B, Lim LL, Kjellstrom T, Seubsman S, Sleigh A Thai Cohort Study Team. Association between occupational heat stress and kidney disease among 37 816 workers in the Thai cohort study (TCS) J Epidemiol. 2012;22:251–60. [PMC free article] [PubMed] [Google Scholar]
- VanDervort DR, López DL, Orantes CM, Rodríguez DS. Spatial distribution of unspecified chronic kidney disease in El Salvador by crop area cultivated and ambient temperature. MEDICC Rev. 2014;16:31–8. [PubMed] [Google Scholar]
- Desalegn B, Nanayakkara S, Harada KH, Hitomi T, Chandrajith R, Karunaratne U, et al. Mycotoxin detection in urine samples from patients with chronic kidney disease of uncertain etiology in Sri Lanka. Bull Environ Contam Tox. 2011;87:6–10. [PubMed] [Google Scholar]
- Wanigasuriya KP, Peiris H, Ileperuma N, Peiris-John RJ, Wickremasinghe R. Could ochratoxin A in food commodities be the cause of chronic kidney disease in Sri Lanka? Trans R Soc Trop Med Hygiene. 2008;102:726–8. [PubMed] [Google Scholar]
- Torres-Lacourt C, Gonzalez M, Vanegas R, Aragon A. Prevalence of chronic kidney insufficiency in the communities of “La Isla” and “Candelaria”, Chichigalpa. Leó Universidad Nacional Autónoma de Nicaragua. 2008 [Google Scholar]
- Sanoff SL, Callejas L, Alonso CD, Hu Y, Colindres RE, Chin H, et al. Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua. Ren Fail. 2010;32:766–77. [PMC free article] [PubMed] [Google Scholar]
- Rugama E. Risk factors that influence the occurence of chronic renal insufficiency in patients admitted at internal medicine service from hospital Oscar Danilo Rosales Arguello in Leon, January – December 2000. Leó Universidad Nacional Autónoma de Nicaragua. 2001 [Google Scholar]
- Jayasumana C, Paranagama P, Agampodi S, Wijewardane C, Gunatilake S, Siribaddana S. Drinking well water and occupational exposure to herbicides is associated with chronic kidney disease, in Padavi-Sripura, Sri Lanka. Environ Health. 2015;14:6. [PMC free article] [PubMed] [Google Scholar]
- Siddarth M, Datta SK, Mustafa M, Ahmed RS, Banerjee BD, Kalra OP, et al. Increased level of organochlorine pesticides in chronic kidney disease patients of unknown etiology: Role of GSTM1/GSTT1 polymorphism. Chemosphere. 2014;96:174–9. [PubMed] [Google Scholar]
- Lebov JF, Engel LS, Richardson D, Hogan SL, Hoppin JA, Sandler DP. Pesticide use and risk of end-stage renal disease among licensed pesticide applicators in the agricultural health study. Occup Environ Med. 2016;73:3–12. [PMC free article] [PubMed] [Google Scholar]
- Wanigasuriya KP, Peiris-John RJ, Wickremasinghe R, Hittarage A. Chronic renal failure in north Central Province of Sri Lanka: An environmentally induced disease. Trans R Soc Trop Med Hyg. 2007;101:1013–7. [PubMed] [Google Scholar]
- Gracia-Trabanino R, Domínguez J, Jansà JM, Oliver A. Proteinuria and chronic renal failure in the coast of El Salvador: Detection with low cost methods and associated factors. Nefrologia. 2005;25:31–8. [PubMed] [Google Scholar]
- Aroonvilairat S, Kespichayawattana W, Sornprachum T, Chaisuriya P, Siwadune T, Ratanabanangkoon K. Effect of pesticide exposure on immunological, hematological and biochemical parameters in Thai orchid farmers—a crosssectional study. Int J Environ Res Public Health. 2015;12:5846–61. [PMC free article] [PubMed] [Google Scholar]
- Wesseling C, Aragón A, González M, Weiss I, Glaser J, Rivard C, et al. Heat stress, hydration and uric acid: A cross-sectional study in workers of three occupations in a hotspot of Mesoamerican nephropathy in Nicaragua. BMJ Open. 2016;6:e011034. [PMC free article] [PubMed] [Google Scholar]
- Wijkstroem J, Jayasumana C, Dassanayake R, Priyawardane N, Godakanda N, Siribaddana S, et al. Morphological and clinical findings in Sri Lankan patients with chronic kidney disease of unknown cause (CKDu): Similarities and differences with Mesoamerican Nephropathy. PLoS One. 2018;13:e0193056. [PMC free article] [PubMed] [Google Scholar]
- Wijkstroem J, Gonza´lez-Quiroz M, Hernandez M, Trujillo Z, Hultenby K, Ring A, et al. Renal morphology, clinical findings, and progression rate in mesoamerican nephropathy. Am J Kidney Dis. 2017;69:626–36. [PubMed] [Google Scholar]
- Gamage CD, Yoshimatsu K, Sarathkumara YD, Kulendiran T, Nanayakkara N, Arikawa J. Serological evidence of hantavirus infection in Girandurukotte, an area endemic for chronic kidney disease of unknown aetiology (CKDu) in Sri Lanka. Int J Infect Dis. 2017;57:77–8. [PubMed] [Google Scholar]
- Murray KO, Fischer RS, Chavarria D, Duttmann C, Garcia MN, Gorchakov R, et al. Mesoamerican nephropathy: A neglected tropical disease with an infectious etiology? Microbes Infect. 2015;17:671–5. [PubMed] [Google Scholar]