ACKD

Toward a Comprehensive Hypothesis of Chronic

Interstitial Nephritis in Agricultural Communities
Carlos Manuel Orantes-Navarro, Rau
l Herrera-Vald
es, Miguel Almaguer-Lo

pez,
Laura Lo
pez-Marı́n, Xavier Fernando Vela-Parada, Marcelo Hernandez-Cuchillas,
and Lilly M. Barba

Over the past 20 years, there has been an increase in chronic interstitial nephritis in agricultural communities (CINAC) not asso-
ciated with traditional risk factors. This disease has become an important public health problem and is observed in several coun-
tries in Central America and Asia. CINAC predominantly affects young male farmers between the third and fifth decades of life
with women, children, and adolescents less often affected. Clinically, CINAC behaves like a chronic tubulointerstitial nephrop-
athy but with systemic manifestations not attributable to kidney disease. Kidney biopsy reveals chronic tubulointerstitial
nephritis with variable glomerulosclerosis and mild chronic vascular damage, with the severity depending on sex, occupation,
and CKD stage. The presence of toxicological, occupational, and environmental risk factors within these communities suggests
a multifactorial etiology for CINAC. This may include exposure to agrochemicals, a contaminated environment, repeated epi-
sodes of dehydration with heat stress, and an underlying genetic predisposition. An understanding of these interacting factors
using a multidisciplinary approach with international cooperation and the formulation of a comprehensive hypothesis are
essential for the development of public health programs to prevent this devastating epidemic.
Q 2016 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Chronic interstitial nephritis in agricultural communities, Chronic kidney disease of unknown causes (CKDu), Pesti-
cides, Dehydration, Heat stress

D iabetes mellitus and hypertension are the two leading

causes of CKD across the globe, particularly in the
developed world. In developing countries, these well-
known etiologies of CKD can be accompanied or
supplanted by other causes of glomerular and tubulointer-
stitial diseases such as infections or injury due to nephro-
toxic drugs, herbal supplements, environmental toxins,
and occupational exposure to pesticides. These factors all
can contribute to the high burden of CKD in developing
nations.1 During the past two decades in certain locations
in Latin America and Asia, there has been an increase in
the prevalence of CKD affecting agricultural communities,
specifically targeting young male agricultural workers
who do not have the traditional risk factors of diabetes
and hypertension. This recently recognized form of CKD
has been termed chronic interstitial nephritis in agricul-
tural communities (CINAC) and has become an important
and devastating public health issue, particularly in Central
America.2-8 In fact, according to The Pan American Health
Organization, Nicaragua and El Salvador have CKD-
related estimated mortality rates of 42.8 and 41.6 deaths
per 100,000, respectively, which is fourfold higher than
any other country in the world with respect to mortality
due to kidney disease. In El Salvador, CKD is the second
most common cause of death in men, with males affected
at three times the rate of females.9
EPIDEMIOLOGICAL CHARACTERISTICS AND
PATHOGENESIS
In El Salvador, a number of epidemiological studies have
estimated the prevalence of CINAC in farming commu-
nities to be between 15% and 21% with a 9% to 13%
prevalence of chronic renal failure. Less than half of those
affected have diabetes mellitus or hypertension. While the
disease predominates in men, it also affects women, chil-
dren, and adolescents who live in these farming commu-
nities regardless of whether they work in agriculture,
and evidence suggests that the kidney disease may begin
in the early stages of life. This increased prevalence of
CKD has been observed in farming communities both in
the highlands and lowlands of El Salvador, suggesting
there may be multiple factors involved.3,10,11
Interestingly, similar findings of CINAC have been
reported worldwide, particularly in Sri Lanka, India, and
Egypt. The etiology of this epidemic of CKD remains
unclear but is thought to include exposure to toxins such
as pesticides and herbicides and repeated episodes of
dehydration which occur in all affected populations.
Other similar risk factors that have been identified in
those affected in differing locations include agricultural
work, male sex, age, poverty, use of well water, over use
of NSAIDs, and histories of snake bites and infections to
a more limited degree.12,13
In farming communities, heavy metals (cadmium and
arsenic) and pesticides are present in well water, floors in
homes, and farmlands and are more concentrated in
From the National Health Institute (INS) and National Renal Health Research
Coordinator, Ministry of Health (MINSAL), San Salvador, El Salvador;
Nephrology Institute, Havana, Cuba; Division of Clinical Research in
Nephrology, Massachusetts General Hospital, Boston, MA; Department of Med-
icine, Mount Sinai St. Luke’s-West, New York, NY; and Division of Nephrology,
Harbor—UCLA Medical Center, Los Angeles, CA.
Financial Disclosure: The authors declare that they have no relevant finan-
cial interests.
Address correspondence to Carlos Manuel Orantes-Navarro, MD, National
Health Institute (INS) and National Renal Health Research Coordinator,
Ministry of Health (MINSAL), San Salvador, El Salvador. E-mail:
doktorantes@gmail.com
Ó 2016 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
http://dx.doi.org/10.1053/j.ackd.2017.01.001

Adv Chronic Kidney Dis. 2017;24(2):101-106 101

102 Orantes-Navarro et al

crop areas. These likely accumulate due to extensive use of birth weight or a genetic predisposition. In Sri Lanka, a
pesticides, including those which have been banned in genomewide association study demonstrated an SNP in
many developed countries, to improve crop yield. The in- the gene encoding sodium-dependent dicarboxylate trans-
crease in CKD incidence in Central America began approx- porter member 3, which conferred increased risk for
imately 20 years ago, concomitant with a significant CINAC with a population attributable fraction of 50%
increase in the use of toxic agricultural chemicals such as and odds ratio of 2.3.28
paraquat, glyphosate, triazines, methamidophos, and Repeated episodes of dehydration due to inadequate
methyl parathion.4,5 The nephrotoxic potential of these intake of fluids while engaged in manual labor in a hot hu-
compounds is known and has been described in the mid climate have been proposed as a cause of CINAC, and
literature.14-19 Pesticide exposure occurs during farmland undoubtedly repeated dehydration may produce kidney
application and from pesticide storage in household damage.29 Suggested pathogenetic mechanisms for
facilities. During spraying, farmers may inhale or dehydration-induced kidney injury include activation of
accidentally ingest pesticides and herbicides, and the aldo reductase-fructokinase pathway in the proximal
their skin may become contaminated with these toxins tubule with subsequent uric acid production resulting
due to the lack of outer garment protection. There is an in proximal tubular injury; this has been replicated in an
association between self-reported use of carbamate pesti- experimental model.30,31 There also may be a role of
cides in a hot and humid environment with a change in rhabdomyolysis.12 Dehydration, caused by inadequate
kidney-related biomarkers and a reduction in GFR. In 20
fluid intake in a hot environment, can affect elimination
the United States, a cohort of 55,580 male licensed pesti- of toxic agents from the blood and increase the concentra-
cide applicators showed a significant association of tion of these agents in the kidney medulla, thus contrib-
chronic exposure to specific pesticides with increased uting to development of kidney injury. While there may
risk of developing end-stage kidney disease.21 Further ev- be a role for dehydration in this epidemic of CKD, dehydra-
idence for a role of toxin tion alone cannot explain the
exposure is the presence of CLINICAL SUMMARY spectrum of this disease,
extrarenal symptoms associ- which affects not only male
ated with CINAC including  Chronic interstitial nephritis in agricultural communities
farmworkers, but also men
urinary dribbling, abnor- (CINAC) typically occurs in young to middle age male who are not farmworkers,
malities in arteries by ultra- farmworkers in regions of Central America and Asia but men in the same geographic
sound, myoclonus and also may occur in women and children. region who do not work in
sensorineural deafness.22 agriculture, women who are
 CINAC is a form of tubulointerstitial nephritis and is a major
Volcanic soil and other natu- employed and not employed
public health crisis in affected countries.
ral contaminants such as in agriculture, and school age
arsenic and hard water also  There are genitourinary, neurologic, and vascular children and adolescents.
may play a role. Although a abnormalities in addition to the kidney disease.
single metal cannot be linked  The pathogenesis of CINAC likely is multifactorial including
CLINICAL
to CINAC, heavy metals pesticide exposure, heat stress, dehydration, environ- CHARACTERISTICS
have been found in excessive mental contaminants, effects of low socioeconomic status, In the early stages of CINAC,
amounts in the urine of agri- and genetic susceptibility. patients may be asymptom-
cultural workers. Jayasu- atic or demonstrate urinary
mana and associates5,23 hesitancy, a thin urinary
hypothesized that the use of glyphosate, an herbicide stream and dysuria. Symptoms become more common in
and strong metal chelater, in conjunction with arsenic CKD 2 and may include genitourinary abnormalities
and the consumption of hard water, might be a cause of such as nocturia, dysuria, post void dribbling, hesitancy,
kidney disease in Sri Lankan agricultural workers. and foamy urine, as well as systemic symptoms such as ar-
When agricultural workers’ clothes become contami- thralgias, abnormal tendon reflexes, muscle cramps, asthe-
nated with pesticides, family members subsequently nias, decreased libido, and fainting.22 At this time, there
may be exposed, particularly women while laundering also may be polyuria with elevated urinary magnesium,
the family clothing.24-26 In affected agricultural sodium, calcium, and phosphorous, with resulting serum
communities, family members may be exposed via electrolyte abnormalities including hyponatremia, hypo-
inhalation or ingestion of these toxins due to kalemia, hypomagnesemia and hypocalcemia, and meta-
contamination of household items or the surrounding bolic alkalosis. As the disease progresses, these
water and soil. In three farming communities in El symptoms progressively intensify with worsening of the
Salvador with a significant prevalence of CINAC, kidney disease. Urine analysis typically is unremarkable
children and adolescents have been shown to have an or shows mild proteinuria, likely of tubular origin with
increased incidence of CKD.10 Ramirez-Rubio and associ- increased b2 microglobulin and tubular markers of injury
ates27 showed that adolescents in an affected community including KIM-1 and NGAL.22,32,33 Urine culture is
in Nicaragua had increased tubular injury associated bio- negative. Kidney imaging shows changes of CKD and
markers despite no involvement with agricultural work. preserved kidney blood flow. No urinary bladder or
Other factors may contribute to childhood CKD in these prostate abnormalities are identified on ultrasound
regions such as poor maternal nutrition resulting in low evaluation.22

Adv Chronic Kidney Dis. 2017;24(2):101-106

 Comprehensive Hypothesis of CINAC 103

As noted above, extrarenal symptoms involving the
cardiovascular, peripheral vascular, and nervous systems
may be present. Most patients are normotensive or have
mildly elevated blood pressure, with a normal EKG and
echocardiogram. On cardiac stress testing, patients typi-
cally have preserved physical capacity, and few have an
abnormal pressor response. Peripheral arterial doppler
studies show few abnormalities of the carotid and aor-
toiliac vessels; however, femoral and particularly tibial
arteries demonstrate irregular walls and atheroscle-
rosis.22 Sensorineural hearing loss is a common finding,
while fundoscopic examination, intraocular pressure,
and visual field testing are normal in the majority of
patients, suggesting an absence of significant microvas-
cular damage as is observed with diabetic or hyperten-
sive retinopathy.22
muscular hypertrophy, smooth muscle vacuolization,
and intimal proliferation within arteries and arterioles.
Interestingly, there are some differences in the extent of
interstitial inflammation and glomerular enlargement
relative to the type of agricultural work; sugarcane
workers demonstrate more tubulointerstitial scarring
and inflammation and less glomerular enlargement
compared with those working with other crops. Immuno-
fluorescence shows no specific immune deposition in the
glomeruli, tubules, or interstitium.34 Electron microscopy
has revealed inclusions in proximal tubular epithelium,
possibly secondary lysosomes or autophagic vacuoles;
however, the pathogenesis of this feature is uncertain
as similar structures are associated with quinine adminis-
tration and their significance is unknown with respect to
CINAC.

HISTOPATHOLOGICAL CHARACTERISTICS PROPOSED CASE DEFINITIONS OF CINAC

Histologic findings are similar in cases of CINAC from
different geographic areas.34-36 The predominant pattern
is of a chronic tubulointerstitial nephritis characterized
by tubular atrophy, interstitial fibrosis, and a variable
interstitial mononuclear inflammatory infiltrate. There
may be associated global glomerulosclerosis, glomeru-
lomegaly, ischemic-appearing glomerular capillary wall
corrugation, and features of vascular injury including
The epidemic itself is defined as an increase in the number
of cases of CKD in agricultural communities, which are
characterized by three general conditions: poverty with
all its repercussions, unhealthy working conditions, and
a contaminated environment. These elements link the dis-
ease to deep rooted socioeconomic circumstances.22 This
CKD epidemic has a double burden. The first is the pres-
ence of well-known traditional causes of CKD (diabetes

DEFINITION OF THE EPIDEMIC

Increase in CKD cases across the world in agricultural communi es
Affects both sexes (male predominance)
Appears early in life
Double burden of the disease
Known tradi onal causes vs. non-tradi onal causes

Possible case (epidemiological criteria)

Pa ent living in an agricultural community with no known history of renal disease
Presence of biomarkers of kidney damage
Decreased glomerular filtra on rate

Probable case (clinical criteria)

Primary or secondary causes of kidney disease cannot be iden fied
Asymptoma c at early stages of the disease
Symptoms: fa gue, cramps, polyuria, nocturia, dysuria, foamy urine, fain ng, joint pain
Signs: occasional hypotension, normal fundoscopy, vascular wall irregulari es predominantly of lower limbs, altered
neurological reflexes, sensorineural hearing loss
Laboratory: low or absent proteinuria, markers of tubular damage, abnormal excre on of electrolytes in urine,
hyponatremia, hypokalemia, hypocalcemia and hypomagnesenemia

Confirmed case (histopathological criteria)

Chronic tubulo-inters al nephri s with glomerulosclerosis and mild chronic vascular changes
.

Figure 1. To make a confirmed diagnosis of chronic interstitial nephritis in agricultural communities (CINAC), it is necessary
to take into account epidemiological, clinical, and histopathological criteria, within the appropriate clinical and geographical
context.

Adv Chronic Kidney Dis. 2017;24(2):101-106

104 Orantes-Navarro et al

mellitus, hypertension, glomerulopathies, and obstructive
uropathy) which affect developed and developing coun-
tries, with an additional second burden due to as yet unde-
termined causes which result in a histopathological
pattern of chronic tubulointerstitial nephritis impacting
those in the targeted areas.2
Examples of cases and their inclusion as part of this
epidemic are detailed below. A person who has lived or
worked in agricultural communities with no known
history of kidney disease and who demonstrates bio-
markers of kidney damage in the urine and/or decreased
glomerular filtration rate is considered to have a possible
case of CINAC based on epidemiology.3,37 Additional
information may further the diagnosis to a probable
case of CINAC, which adds clinical criteria to the
epidemiology. This would encompass a patient with
possible CINAC in whom a primary or secondary cause
of kidney disease has not been identified and who
progresses from an early asymptomatic stage to
exhibiting symptoms of fatigue, cramps, polyuria,
nocturia, dysuria, foamy urine, fainting, joint pain and/
or signs including occasional hypotension, mild cardiac
disorders with predominant lower extremity peripheral
vascular damage, a normal funduscopic examination,
altered neurological reflexes, and sensorineural hearing
loss. None of these findings should be a consequence of
the stage of CKD. Additional findings may include no
or minimal proteinuria, the presence of tubular
injury markers such as b2 microglobulin, and abnormal
urinary electrolyte excretion with associated hyp-
onatremia, hypokalemia, hypomagnesemia, and/or
hypocalcemia.3,22 A confirmed case of CINAC fulfills the
epidemiological and clinical criteria of CINAC denoted
above and in whom a kidney biopsy demonstrates the
histopathological pattern of chronic tubulointerstitial
nephritis with or without secondary glomerulosclerosis
and vascular damage.34 Figure 1 depicts how these case
definitions fit within the broad diagnostic spectrum of CI-
NAC from the community level to the individual.
COMPREHENSIVE HYPOTHESIS OF CINAC
PATHOGENESIS
CINAC is a multifactorial disease, predominantly
affecting young male farmers, and fewer numbers of
nonfarming women, adolescents, and children. The wide-
spread reach of CINAC within farming communities in

Social Determinants of Health:

CondiƟons of Poverty

Unhealthy
ealthyy working
worki g condiƟons
Environmental
ntal PolluƟon
Harsh agricultural Hot and hu
humid
Air Water Food Indiscriminate use of environment
Clothing working conditions
Human behavior agrochemicals

Polluted Agricultural
Periodic toxic Heatt stre
stress &
drinking occupation
exposure Direct and indire
indirect contact Dehydration
water
with agrochemicals
Entrance
ce routes
ro Ischemia
chem

Concentration
ation of Molecular
Mo
M ecula cell
Ingestion
inhalation Skin contact toxins in the kidneyss changes
c

High CHRONIC
C C EXPOSURE
EXP Low
level level Chronic kidney
Ch ney
damage
Farmers
armers
s NEPHROTOXICITY
OTOX Y Genera
G
General Risk Group
Po
opulati
Population

• Sugar cane cuƩer

CINAC
• Farmer Non-sugar cane cuƩer
Low birth weight • Non-farmer that lives or lived in
agricultural communiƟes

Fetal life Newborn Infant Toddler Child Adolescent Adult Elderly

Gene c factors Appears early in life

Family history, Gender Double burden of the disease
Living in the agricultural community Known tradi onal causes & non-tradi onal causes

Figure 2. Several factors play a role in the etiology of chronic interstitial nephritis in agricultural communities (CINAC), with
environmental contamination by nephrotoxic agents as the pathogenic trigger. Different levels of exposure to this pollution
may predispose susceptible individuals to kidney damage. Superimposed unhealthy working conditions, including dehydra-
tion, provide additional risk but cannot explain the epidemic alone. For patients living in these communities, the aggregate
injury of long-term exposure to these insults results in the development of CINAC.

Adv Chronic Kidney Dis. 2017;24(2):101-106

 Comprehensive Hypothesis of CINAC
Central America and Asia suggests the presence of envi-
ronmental risk factors associated with the occupation of
their residents. Those living in these agricultural commu-
nities are exposed to the same risk factors as the general
population, with additional exposure occupational risks.
Environmental natural or man-made toxic agents (heavy
metals, pesticides, and chemicals and/or microbial
substances) in the air, soil, or water may be subjected
to transformation by climate, topography, and soil
use.14-17,24,33,36,38 These may spread to the wider farming
community via air, water soil displacement, or
absorption into the food chain. These toxic agents can
then affect a susceptible subject who is exposed to
unhealthy lifestyles and harsh working conditions such
as dehydration and heat stress. Farmers likely have more
concentrated and chronic exposure via drinking water,
inhalation, ingestion, or skin contact while working in
the fields. The intensity of the exposure may vary,
ranging from high level (repeated exposure affecting
primarily farmers) to a low level (chronic exposure
affecting the general population) leading to repeated
episodes of subclinical kidney injury. On a molecular
level, toxins can affect the kidney tissue through direct
tubular cell toxicity or alterations in intrarenal blood
flow producing secondary tubular damage leading to
CINAC.14,23 Other factors putting this population at
increased risk for CKD include low birth weight,
infectious diseases, traditional risk factors, use of
NSAIDs, and nephrotoxic medicinal herbs. Finally, there
may be genetic susceptibility among the affected
populations. A comprehensive hypothesis for the
development of CINAC is summarized in Figure 2.
CONCLUSIONS
The medical and scientific communities recognize CI-
NAC as a public health crisis. The use of the unifying
term CINAC in concert with our comprehensive hypoth-
esis of its pathogenesis and proposed case definitions
provides a framework for continued collection and anal-
ysis of risk factor data. Establishing a set of criteria for
public health surveillance in different regions of the
world with the same epidemic pattern (eg, El Salvador
and Sri Lanka) will allow reporting from differing
geographic locations with similar disease patterns.12 It
is hoped that identification of multiple potential risk fac-
tors will provide public health officials and decision
makers opportunities for early identification, interven-
tion, and ultimately prevention of CINAC in socially
vulnerable individuals in rural communities. In addition,
there are social and environmental implications with re-
gard to human rights in the context of adequate occupa-
tional health and safety.
CINAC appears to be a complex disease that develops
in susceptible individuals working in agriculture or
within that environment to a lesser extent. It is of critical
importance to have a broad collaboration and multidisci-
plinary approach that seeks to strengthen health services,
work force training, and access to health technology,
medications, and medical surveillance through interna-
tional cooperation.
Adv Chronic Kidney Dis. 2017;24(2):101-106
105
REFERENCES
1. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global
dimension and perspectives. Lancet. 2013;382(9888):260-272.
2. Almaguer M, Herrera R, Orantes CM. Chronic kidney disease of un-
known etiology in agricultural communities. MEDICC Rev.
2014;16(2):9-15.
3. Orantes Navarro CM, Herrera Vald
es R, L
opez MA, et al. Epidemi-
ological characteristics of chronic kidney disease of non-traditional
causes in women of agricultural communities of El Salvador. Clin
Nephrol. 2015;83(7 Suppl 1):24-31.
4. Jayasumana C, Gajanayake R, Siribaddana S. Importance of arsenic
and pesticides in epidemic chronic kidney disease in Sri Lanka. BMC
Nephrol. 2014;15:124.
5. Jayasumana C, Gunatilake S, Senanayake P. 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 En-
viron Res Public Health. 2014;11(2):2125-2147.
6. Jayasumana C, Fonseka S, Fernando A, et al. Phosphate fertilizer is a
main source of arsenic in areas affected with chronic kidney disease
of unknown etiology in Sri Lanka. Springerplus. 2015;4:90.
7. Peraza S, Wesseling C, Aragon A, et al. Decreased kidney function
among agricultural workers in El Salvador. Am J Kidney Dis.
2012;59(4):531-540.
8. Cerdas M. Chronic kidney disease in Costa Rica. Kidney Int Suppl.
2005;(97):S31-S33.
9. Organization PAHO. Chronic kidney disease in agricultural com-
munities in Central America. 2013:1–3.
10. Orantes CM, Herrera R, Almaguer M, et al. Chronic kidney disease in
children and adolescents in Salvadoran farming communities: Nefro-
Salva Pediatric Study (2009–2011). MEDICC Rev. 2016;18:15-21.
11. Herrera Vald
es R, Orantes CM, Almaguer L
opez M, et al. Clinical
characteristics of chronic kidney disease of non-traditional causes
in women of agricultural communities in El Salvador. Clin Nephrol.
2015;83(7 Suppl 1):56-63.
12. Jayasumana C, Orantes C, Herrera R, et al. Chronic interstitial
nephritis in agricultural communities: a worldwide epidemic with
social, occupational and environmental determinants. Nephrol Dial
Transplant. 2016.
13. Bandarage A. Political economy of epidemic kidney disease in Sri
Lanka. SAGE Open. 2013;3(4):1-13.
14. Chaumont A, Nickmilder M, Dumont X, Lundh T, Skerfving S,
Bernard A. Associations between proteins and heavy metals in urine
at low environmental exposures: evidence of reverse causality. Tox-
icol Lett. 2012;210(3):345-352.
15. Gonick HC. Nephrotoxicity of cadmium & lead. Indian J Med Res.
2008;128(4):335-352.
16. Edwards JR, Prozialeck WC. Cadmium, diabetes and chronic kidney
disease. Toxicol Appl Pharmacol. 2009;238(3):289-293.
17. J€arup L, Akesson A. Current status of cadmium as an environmental
health problem. Toxicol Appl Pharmacol. 2009;238(3):201-208.
18. Kalahasthi RB, Rajmohan H, Rajan B, Kumar MK. Urinary N-acetyl-
beta -D-glucosaminidase and its isoenzymes A & B in workers
exposed to cadmium at cadmium plating. J Occup Med Toxicol.
2007;2:5.
19. Sabath E, Robles-Osorio ML. Medio ambiente y ri~
n: nefrotoxici-
no
dad por metales pesados (Renal health and the environment: heavy
metal nephrotoxicity). Revista Nefrologia Organo. 2012;32(3):279-286.
20. García-Trabanino R, Jarquín E, Wesseling C, et al. Heat stress, dehy-
dration, and kidney function in sugarcane cutters in El Salvador–a
cross-shift study of workers at risk of Mesoamerican nephropathy.
Environ Res. 2015;142:746-755.
21. 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. Oc-
cup Environ Med. 2016;73(1):3-12.
106 Orantes-Navarro et al
22. Herrera R, Orantes CM, Almaguer M, et al. Clinical characteristics of
chronic kidney disease of nontraditional causes in Salvadoran
farming communities. MEDICC Rev. 2014;16(2):39-48.
23. Jayasumana MA, Paranagama P, Amarasinghe M, et al. Possible link
of chronic arsenic toxicity with chronic kidney disease of unknown
etiology in Sri Lanka. J Nat Sci Res. 2013;3(1):64-73.
24. Rib
o A, Quinteros E, Mejía R, Jovel R, L
opez D. Contaminaci
on de
ars
enico en suelos, sedimentos y agua en la regi
on del Bajo Lempa,
El Salvador. Paper presented at: Libro de Resumen. VII Congreso de
la Red Latinoamericana de Ciencias Ambientales. San Carlos, CR:
Universidad Nacional de Costa Rica 2013.
25. Mejía R, Quinteros E, L
opez A, et al. Pesticide-handling practices in
agriculture in El Salvador: an example from 42 patient farmers with
chronic kidney disease in the Bajo Lempa region. Occup Dis Environ
Med. 2014;2:56-70.
26. VanDervort DR, L
opez DL, Orantes CM, Rodríguez DS. Spatial dis-
tribution of unspecified chronic kidney disease in El Salvador by
crop area cultivated and ambient temperature. MEDICC Rev.
2014;16(2):31-38.
27. Ramírez-Rubio O, Amador JJ, Kaufman JS, et al. Urine biomarkers
of kidney injury among adolescents in Nicaragua, a region affected
by an epidemic of chronic kidney disease of unknown aetiology.
Nephrol Dial Transplant. 2016;31(3):424-432.
28. Nanayakkara S, Senevirathna ST, Abeysekera T, 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(1):28-38.
29. Torres C, Arag
on A, Gonz
alez M, et al. Decreased kidney function of
unknown cause in Nicaragua: a community-based survey. Am J Kid-
ney Dis. 2010;55(3):485-496.
30. Roncal Jimenez CA, Ishimoto T, Lanaspa MA, et al. Fructokinase ac-
tivity mediates dehydration-induced renal injury. Kidney Int.
2014;86(2):294-302.
31. Roncal-Jimenez C, García-Trabanino R, Barregard L, et al. Heat
stress nephropathy from exercise-induced uric acid crystalluria: a
perspective on mesoamerican nephropathy. Am J Kidney Dis.
2016;67(1):20-30.
32. De Silva PM, Mohammed Abdul KS, Eakanayake EM, et al. Urinary
biomarkers KIM-1 and NGAL for detection of chronic kidney dis-
ease of uncertain etiology (CKDu) among agricultural communities
in Sri Lanka. PLoS Negl Trop Dis. 2016;10(9):e0004979.
33. C
ardenas-Gonz
alez M, Osorio-Y
an~ez C, Gaspar-Ramírez O, et al.
Environmental exposure to arsenic and chromium in children is
associated with kidney injury molecule-1. Environ Res.
2016;150:653-662.
34. L
opez-Marín L, Ch
avez Y, García XA, et al. Histopathology of
chronic kidney disease of unknown etiology in Salvadoran agricul-
tural communities. MEDICC Rev. 2014;16(2):49-54.
35. Selvarajah M, Weeratunga P, Sivayoganthan S, Rathnatunga N,
Rajapakse S. Clinicopathological correlates of chronic kidney dis-
ease of unknown etiology in Sri Lanka. Indian J Nephrol.
2016;26(5):357-363.
36. Wijkstr€om J, Leiva R, Elinder CG, et al. Clinical and pathological
characterization of Mesoamerican nephropathy: a new kidney dis-
ease in Central America. Am J Kidney Dis. 2013;62(5):908-918.
37. Orantes CM, Herrera R, Almaguer M, et al. Epidemiology of chronic
kidney disease in adults of Salvadoran agricultural communities.
MEDICC Rev. 2014;16(2):23-30.
38. Soderland P, Lovekar S, Weiner DE, Brooks DR, Kaufman JS.
Chronic kidney disease associated with environmental toxins and
exposures. Adv Chronic Kidney Dis. 2010;17(3):254-264.
Adv Chronic Kidney Dis. 2017;24(2):101-106