CORE Group Global Health Practitioner Conference 2019

1. CKDu epidemic in Mesoamerica:
an occupational disease
Catharina (Ineke) Wesseling
IMM, Karolinska Institutet, Sweden
La Isla Network, Washington D.C., USA

2. Mesoamerican nephropathy (MeN)
• A severe CKD epidemic unrelated
to hypertension, diabetes or
obesity
• Tropical lowlands along the Pacific
coast from Mexico to Panama
• One estimate of 20,000 deaths by
2012
• Main hypotheses:
• Toxins: pesticides, metals
• Heat stress and chronic dehydration
• Unknown ------ Multifactorial
Along the Pacific coast, in the lowlands

3. Disentanglement of a multifactorial etiology is of crucial
importance for effective interventions in those causal components
that are identified
Let us keep in mind
We are in the presence of an epidemic with tens of thousands
of premature deaths
Even in the presence of multiple causes, there must be a
very STRONG driver

4. Early evidence
• Mid 1990s: The occupational nature of the disease was noted by clinicians and workers
• Costa Rica: “Nefropatía del cañero / sugarcane worker nephropathy”
• El Salvador: Hospital case series showed hundreds of young, male agricultural workers with
kidney failure without known cause
• Nicaragua: Vital and health statistics showed large male / female differences, especially in
sugarcane areas
0
10
20
30
40
Guanacaste
Costa Rica…
Men
0
10
20
30
40
Women
Time trend CKD
mortality in CKDu
area in Costa Rica
vs rest of the
country
(Wesseling et al, 2016)
Green revolution
Global warming
Plantation agriculture
Migration
Informal work

5. Outbreak study by company physician at sugarcane enterprise
Nicaragua (Zelaya, 2001)
• In 1999 the number of job applicants with high SCr became alarming:
‘outbreak study’ during zafra 2000-2001 …
• Conclusions
• Exhausting physical work in high environmental temperatures without a
proper hydration program predisposes to heat fatigue syndrome (insolation),
which is an important factor that leads to CKD
• Awkward positions for cane cutters during long workdays with poor hydration
lead to excessive intake of NSAIDs

6. Prevalence studies followed with data indicating occupational etiology
• Men much more affected than women in the general population
• Women similarly affected within occupational categories
• Not all agricultural worker populations reported with high prevalences of kidney dysfunction:
• High prevalence: sugarcane cutters and other sugarcane field workers, any agricultural field workers,
cotton workers, banana workers, and rice and corn farmers
• No excess: subsistence farmers in high risk areas without history of plantation work:
control over working conditions, work in cooler hours, self-pacing
• Also non-agricultural worker populations moderate to high prevalence of kidney dysfunction:
• Fishermen 7%, shrimp farmers 10%, construction workers 5-15%, miners 6-16%; port workers with heavy
labor 8%, and brick makers 12%
Common characteristic: hot occupations
HIGH WORKLOAD COUPLED TO ENVIRONMENTAL HEAT

7. 0
5
10
15
20
25
30
Triglycerides >200 mg
/dL
Blood pressure
>140/90
BMI >30 kg/m2 SCr >1.20 mg/dL eGFR CKD-EPI <80
ml/min/1.73m2
Proteinuria >30
mg/dL
Cane cutting Construction work Farming
%
Nicaraguan sugarcane cutters compared to construction workers and
farmers, age 18 – 39, León, Nicaragua, 2013 (n=194)
Cutters better general health
(Wesseling et al, BMJ Open, 2016)
Cutters with worse kidney function

8. Pesticide and metal studies negative
• Review on pesticides and CKD:
• Scarce or no evidence for pesticides as an important etiology, but poor exposure assessment (Valcke et al, 2017)
• Two following studies with good exposure assessment negative
• 2,4-D and glyphosate exposure in work environment in sugarcane workers of the WE Program was very low (Curwin et al, 2016,
NIOSH study)
• No associations with kidney decline for 12 common pesticides and 12 metals in a nested case-control study of the Nicaraguan
community cohort (Smpokou et al, 2019)
• Metals negative
• Low serum levels of cadmium, arsenic, lead, urenium and other metals in the WE Program participants in El Salvador (Jakobsson et
al, manuscript)
• No associations with kidney dysfunction in Nicaragua among sugarcane workers, construction workers, miners and port workers
with heavy labor (McClean et al, 2012)
• In general: TOXIN levels in affected regions, both measured in environmental and human samples are
below international tolerances and below levels that would produce other evident health effects.
• Conclusion: Toxins may contribute but are not the strong drivers of the epidemic of CKDu in
Mesoamerica

9. Cross-shift observations in sugarcane workers
Study Setting Findings / conclusion pro-occupational
etiology
Crowe et al,
2014
Costa Rica
Cane cutters (n=56)
3 x 1 week, midharvest
Urine, dipstick and microscopy
-Clear evidence of dehydration and kidney
injury among heat stress exposed workers.
-Overnight recovery was insufficient
García-
Trabanino et
al, 2015
El Salvador
Cane cutters (n=189)
End of harvest
Phys exam, urine, blood
Changes for blood pressure and kidney-
related serum and urine biomarkers involved
in maintaining water and electrolyte balance
were associated with heat and workload
Wesseling et
al, 2016
Nicaragua
Cane cutters (n= 29), D1, D6, Wk 9
Administrative referents (n=25), start and
end of harvest
Phys exam, urine, blood
Dehydration cross-shift among cutters is
clear and repeated among cutters and not
among administrative workers
Wegman et
al, 2018
El Salvador
Cane cutters (n=40)
Pre- and post intervention (midharvest)
and end of harvest
Phys exam, urine, blood
-Cases of AKI developed
-Cross-shift decline in eGFR related to heat
and workload
-Positive effect intervention on reducing
cross-shift kidney function decline.
Sorensen et
al, 2018
Guatemala
Sugarcane field workers (n=105)
1/mth, 3 x towards end harvest
Urine, blood
High prevalence of acute decline in eGFR in
well-hydrated workers
Without exception,
studies concluded that
cross-shift physiologic
and biomarker changes
were compatible with
heat stress and
dehydration

10. Longitudinal observations in workers
Study Setting Findings / conclusion pro-
occupational etiology
Laws et al, 2015
Laws et al, 2016
Nicaragua
Cross-harvest cohort in five job
categories of sugarcane field
workers and two categories of
non-field workers (n=284)
-eGFR decline and increase in markers of
injury acute tubular differed by job category
-Findings in accordance to heat stress in the
job categories
-Protective effect from electrolytes
Wesseling et al,
2016
Nicaragua
Cutters (n= 29), Day 1, Day 6,
Week 9
Administrative workers (n=25),
start - end of harvest
Marked decline in kidney function among
cutters but not in the referent population
Butler-Dawson et
al, 2017
Guatemala
Cross-harvest cohort of 330
cutters
-Decline in eGFR in 37% of young male
cutters (6% with a decline in eGFR > 20%)
-3% declined over the harvest to eGFR <60
ml/min/1.73m2
Gallo-Ruiz et al,
2019
Nicaragua
Brick makers (n= 257),
4-month follow-up
-High prevalence of CKD (twice eGFR<60
ml/min/1.73m2, ≥ 3 months apart)
-Risk higher among highest heat exposed
(ovens)
- Low water intake and longest work week
associated with decline in eGFR over the
follow-up
Without exception,
studies found decline in
eGFR over the follow-up
among heat exposed job
categories, more severe
in workers with the
highest heat exposures

11. Community cohort in Nicaragua with 2-year follow-up
Decline in Kidney Function among Apparently Healthy Young Adults at Risk of
Mesoamerican Nephropathy (Gonzalez-Quiroz et al, 2018)
020406080100120140160
Estimatedglomerularfiltrationrate(mL/min/1.73m
2
)
0 0.5 1 1.5 2
Time in study (years)
Stable kidney function
(n = 213, I = 113.3, S = -0.3)
020406080100120140160
Estimatedglomerularfiltrationrate(mL/min/1.73m
2
)
0 0.5 1 1.5 2
Time in study (years)
Rapid decline in kidney function
(n = 25, I = 109.5, S = -9.1)
020406080100120140160
Estimatedglomerularfiltrationrate(mL/min/1.73m
2
)
0 0.5 1 1.5 2
Time in study (years)
Renal dysfunction at baseline
(n = 25, I = 55.6, S = -1.9)
Rapid decline in 10% of healthy men at
baseline and 3% of women
Associations with rapid decline:
• Agricultural work, outdoor work and lack
of shade
Sensitivity analyses:
• Cane and seed cutting and fever in the last
6 months
No association with general questions on
perceived heat exposures
No pesticide associations
Conclusion: Besides occupational factors also
non-occupational factors may contribute

12. Evidence for non-occupational etiology
• Some reports of women with MeN, who were not occupationally active
• Limited evidence of early kidney injury in children in vulnerable agricultural
communities
• Associations with non-occupational risk factors
• Most frequently age
• Smoking, alcohol intake, diabetes, hypertension, kidney stones, NSAIDs mostly negative or
inconsistent across studies.
Non-occupational risk factors did not emerge as suspects for being a
primary driver of the occurrence of MeN in any of the studies
conducted to date

13. Therefore: LIN started intervention studies
to prevent heat stress
• Two intervention studies in the region
• WE Program in El Salvador
• Adelante Initiative in Nicaragua
• Intervention studies are complex
o Effectiveness of the different components to prevent heat exposure
 physical work load, work tools, water, rest, shade, sanitation at work, work
organization, payment scheme (piece work)
o Feasibility
o Adequacy of implementation
o Simultaneously study etiology

14. 88
92
96
100
104
5-8 Nov 7-9 Jan 18 Fbr 8-10 Apr
Mean eGFR (as percentage of baseline
value) over the course of the Harvest
Inland Coastland
WE-Program in El Salvador: Water - Rest - Shade and Efficiency
intervention for sugarcane cutters (Bodin et al, 2016; Wegman et al 2018)
With intervention
N=40
Without intervention
N=40

15. Adelante Initiative in Nicaragua
WRS in sugarcane field workers (n=530), first year assessment
Incident Kidney Injury (IKI) across harvest: overall 12%
8% in those who finished harvest and 32% in drop outs
The same environmental heat for the different job categories
Job category Physical
activity
Only harvest finishers Including drop-outs Adjusted
Incidence Ratio
(95% CI)
#
N=427
IKI measured
%
#
N=530
IKI measured+
reported
%
Burned cane cutters Very high 128 21 158 27 11.9 (4.0 – 35.8)
Seed cutters High 148 3 190 8 3.5 (1.2 – 10.7)
Irrigation repair workers Intermediate 109 0 128 2
1
Field support staff Low 42 0 54 2
Current preventive measures are insufficient for categories with highest physical workload

16. Conclusions
• In Central America, sugarcane cutters have provided the bulk of the data to understand
CKDu related to heat stress
• Sentinel occupational population, showing the tip of the iceberg of what occurs in other
populations less visibly
• Non-occupational causal factors certainly must contribute but:
• For an epidemic as devastating as MeN there must be a strong driver
All hard evidence points to
a work-related disease caused by occupational heat stress

17. THANK YOU