Nihms 731136
Nihms 731136
Author manuscript
Trop Med Int Health. Author manuscript; available in PMC 2017 January 01.
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Summary
Objectives—Recent studies in Central America indicate that mortality attributable to chronic
kidney disease (CKD) is rising rapidly. We sought to determine the prevalence and regional
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variation of CKD and the relationship of biologic and socioeconomic factors to CKD risk in the
older-adult population of Costa Rica.
Methods—We used data from the Costa Rican Longevity and Health Aging Study (CRELES).
The cohort was comprised of 2657 adults born before 1946 in Costa Rica, chosen through a
sampling algorithm to represent the national population of Costa Ricans >60 years of age.
Participants answered questionnaire data and completed laboratory testing. The primary outcome
of this study was CKD, defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/
1.73m2.
Results—The estimated prevalence of CKD for older Costa Ricans was 20% (95% CI 18.5 –
21.9%). In multivariable logistic regression, older age (adjusted odds ratio [aOR] 1.08 per year,
95%CI 1.07–1.10, p<0.001) was independently associated with CKD. For every 200 meters above
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sea level of residence, subjects’ odds of CKD increased 26% (aOR 1.26 95% CI 1.15–1.38,
p<0.001). There was large regional variation in adjusted CKD prevalence, highest in Limon (40%,
95% CI 30%–50%) and Guanacaste (36%, 95% CI 26–46%) provinces. Regional and altitude
effects remained robust after adjustment for socioeconomic status.
Corresponding Author: Meera Nair Harhay, 245 North 15th Street, New College Building, Mail Stop 437, Philadelphia, PA 19102,
USA. Phone +1-215-779-7553, [email protected].
Harhay et al. Page 2
needed to explore the potential association of geographic and environmental exposures with the
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risk of CKD.
Keywords
Chronic Kidney Disease; Costa Rica; Epidemiology; Mesoamerican Nephropathy; Tropical
Chronic Disease; Altitude
Introduction
Many developing countries have experienced a surge in chronic disease states, including
chronic kidney disease (CKD).1–3 CKD is a major risk factor for cardiovascular morbidity
and mortality, and among the world’s growing elderly population, CKD is also an
independent risk factor for physical and cognitive dysfunction and poor quality of life.4,5 As
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In Central America, the rates of renal replacement therapy and transplantation for CKD have
steadily increased in recent years, and some countries have reported alarming increases in
mortality rates attributed to CKD.16,17 Costa Rica is a middle-income country in Central
America that is known for its population’s longevity, social development, universally
available healthcare, and decline in mortality from communicable disease.18 However, a
study of Costa Rican vital statistics revealed that age-standardized mortality rates from CKD
doubled among men and quadrupled among women from 1970 to 2012.19 Based on 2011
census data, the Costa Rican population is comprised of 4.3 million inhabitants, 7% aged 65
years and older, with 24% residing in the three lowland and primarily agricultural provinces
of Guanacaste and Puntarenas on the Pacific coast and Limón on the Caribbean coast
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(Figure 1). The remaining population resides in four more urbanized central provinces,
namely San Jose, Alajuela, Cartago and Heredia, with the majority of the population living
in the highlands of the Central Valley, including the metropolitan area of San Jose.20
Previous work has highlighted the increasing prevalence of traditional CKD risk factors in
Costa Rica, including an aging population,21 and increased prevalence of hypertension22 and
diabetes.23 A recently described nephropathy called CKDnT (CKD of nontraditional
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Harhay et al. Page 3
causes)24,25 has been described at epidemic levels among young Costa Ricans and other
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Central Americans without traditional CKD risk factors, and may partially explain the rising
mortality from CKD in the region. Hypotheses for the causative factor of CKDnT include
toxic exposures (e.g., traditional medicines, pesticides),26 geographic factors (e.g., heat and
altitude effects), and harsh working conditions of agricultural workers.14,27–30
As the population worldwide is aging, there is a need to identify potential risk factors for
CKD in older populations in developing countries like Costa Rica, including geographic,
socioeconomic and educational differences among citizens that drive health behaviors32 and
disparate access to medical care.33 Therefore, using nationally representative data from the
Costa Rican Study of Longevity and Healthy Aging (CRELES), our objectives were to
determine: (1) the prevalence levels of CKD in the older-adult population of Costa Rica, (2)
the relationship of biologic and socioeconomic factors to CKD risk, and (3) the regional
variation in CKD prevalence in Costa Rica.
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Methods
Data Source and Study Participants
Our data source was the publicly available database of the Costa Rican Study of Longevity
and Healthy Aging (CRELES).34 CRELES is a longitudinal study of a nationally
representative sample of 2827 Costa Rican adults born in or prior to 1946. We used data
from the first two waves of surveys, which took place mostly in 2005 and 2007. The first
survey wave of CRELES collected data on 2827 individuals. The sampling strategy for the
study, which included oversampling of older ages, has been described elsewhere.35
Approximately 5% of participants declined to provide the blood sample in each wave. The
final sample in the first survey wave comprised 2657 individuals (94%) who had laboratory
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creatinine) according to the methods described elsewhere, which include linear adjustments
to have comparable measurements across laboratories.36 Serum creatinine measurements
were calibrated using the Roche method for Isotope Dilution-Mass Spectometry.37 The
institutional review board of the University of Costa Rica granted human subjects approval
to CRELES and all participants granted their informed consent by means of their signature.
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Definition of CKD
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We calculated estimated glomerular filtration rate (eGFR) based on the 2009 CKD-EPI
equation.38,39 The CKD-EPI equation utilizes data on participant age, sex, and race, though
race was not relevant in the current analysis. We then categorized eGFR categories per the
2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, as follows: G1)
eGFR≥90 ml/min/1.73m2, G2) eGFR ≥60 and <90 ml/min/1.73m2, G3a) eGFR ≥45 and <60
ml/min/1.73m2, G3b) eGFR ≥30 and <45 ml/min/1.73m2, G4) eGFR< 30 and ≥15 ml/min/
1.73m2, G5) <15 ml/min/1.73m2. As urine albumin data was not available to identify CKD
at higher eGFR levels, only participants with eGFRs in categories G3a, G3b, G4, and G5
were categorized as having CKD.40
and Costa Rican older adults: province of residence19 and altitude of residence above sea
level.30 We also explored the association of socioeconomic status (SES, based on a country-
specific wealth scale) and educational attainment on the risk of CKD. The residential
altitude of the CRELES respondents was an ecological variable representing the mean
altitude of their district of residence, which is the smallest geographic unit in Costa Rica
(i.e., there are 473 districts among the seven Costa Rican provinces).
pressure (SBP ≥ 150 mmHg or DBP ≥ 90 mmHg),42 and obesity (defined as having a body
mass index ((BMI) higher than 30 kg/m2). We adjusted for reported medication use for
diabetes, hypertension, or hyperlipidemia. The following variables were also considered
potential confounders in this analysis: sex, age, income, years of education, recent physician
visits, and smoking history.
Statistical analysis
To identify the association of our hypothesized risk factors with CKD among elderly Costa
Ricans, we first explored their univariate associations with CKD. Then, we estimated the
prevalence of CKD by sex, age, altitude and province. Finally, we fit multivariable logistic
regression models for CKD using covariates that were significant (p-value threshold <0.2) at
the univariate level. To identify regions with risk of CKD above that expected by traditional
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risk factors, we estimated CKD prevalence per region after adjustment for covariates
identified in our multivariable model. Statistical analyses were conducted using STATA MP
version 13.0 (Stata Corporation, 2013). Descriptive statistics included proportions for
categorical variables, and means for continuous variables, with 95% confidence intervals
(CI). All statistical analyses took into account differential sampling weights.
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Sensitivity Analysis
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As the CKD definition based on KDIGO guidelines includes evidence of consistently low
eGFR in repeat testing after 90 days,40 we performed a sensitivity analysis utilizing repeat
measures of eGFR from the second wave of CRELES, conducted close to two years later.
Results
Bivariate Analysis
The first survey wave of CRELES collected data on 2827 individuals, of whom 2657 (94%)
had laboratory data collected on renal function. Of these individuals, 744 survey participants
had evidence of CKD by eGFR criteria (eGFR<60 ml/min/1.73m2).40 The average age of
the study sample was 76 years (standard error 1.3 years); 45% were male and 20% were
diabetic. Subjects with CKD were more likely to be older, female, diabetic, and hypertensive
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(Table 1). Subjects with CKD also had lower educational attainment, higher systolic blood
pressure, and were more likely to be taking medications for diabetes, hypertension, and
hyperlipidemia. A greater proportion of subjects with CKD had recently seen a physician
and lived at higher altitude. There were also differences in the proportion of subjects with
CKD between provinces. There were no significant (at the p<0.05 level) bivariate
associations between CKD and income or wealth status.
prevalence of stage 3a was 14% (95% CI: 12–16%) among males and 20% (95% CI: 17–
22%) among females, whereas stages 3b-5 CKD were present in 6% (95% CI: 4–7%) of
males and 6% (95% CI: 5–7%) of females. Women exhibited a higher CKD prevalence than
men at all ages, although among individuals over the age of 80 years, the difference between
sexes was no longer statistically significant.
and gender, living at higher altitudes was independently associated with higher risk of CKD
(aOR 1.28 for every 200 meter increase above sea level, 95% CI: 1.13–1.83, p<0.001). Also,
compared to the capital province of San Jose, residence in Guanacaste (aOR 3.43, 95% CI:
1.84–6.38, p<0.001), Puntarenas (aOR 1.99, 95% CI: 1.14–3.48, p=0.02), or Limon (aOR
4.84, 95% CI: 2.56–9.15, p<0.001) was independently associated with higher risk of CKD.
Adding socioeconomic status (SES) and comorbidity risk factors to the multivariable model
did not substantively change our findings of altitude and regional effects, but did attenuate
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the effect of female gender on CKD risk. In the fully adjusted model, other risk factors for
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CKD included having poorly controlled blood pressure (aOR 1.60, 95% CI: 1.10–2.32,
p=0.01), taking diabetes medication (aOR 1.73, 95% CI: 1.04–2.87, p=0.04), hypertension
medication (aOR 1.52, 95% CI: 1.06–2.18, p=0.02), and lipid-lowering medication (aOR
1.48, 95% CI: 1.10–1.99, p=0.01). The adjusted CKD prevalence increased monotonically
from 10.4% (95% CI: 6.8–13.9%) for regions below 200 meters to 26.5% (95% CI: 18.2–
34.1%) for regions at 1400–1799 meters above sea level (Figure 3). There were not enough
observations of subjects living at altitudes higher than 1800 meters (N=23) to produce stable
estimates in this model.
CKD prevalence rates were observed in Alajuela and Puntarenas (14% and 15%,
respectively), while the highest prevalence rates were observed in Cartago and Limon (28%
and 25%, respectively). However, after further adjusting for the effect of altitude, San Jose,
Alajuela, and Heredia had the lowest CKD prevalence (16% for all), and Guanacaste and
Limon had the highest (37% and 42%, respectively).
Sensitivity Analysis
Appendix 1 reports the results of a sensitivity analysis incorporating available longitudinal
data on subjects, collected from the second survey wave of CRELES (conducted 2 years
after the first wave). 77% of subjects had repeat eGFR measures in the second survey wave;
the resulting analytical sample for the sensitivity analysis contained 4,740 observations. We
found that the strength of the associations observed between age, region, altitude, and CKD
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risk remained consistent and statistically significant, although the observed elevated risk of
CKD in Limon and Guanacaste provinces was lower (aOR of 2.72 vs. 4.53 and 2.66 vs.
3.65, respectively). The use of the two waves of survey data resulted in slightly higher
estimates of national CKD prevalence: 26% (95% CI: 24–28%) among all older adults, 23%
(95% CI: 20–25%) among older males and 29% (95% CI: 27–34%) among older females.
Discussion
The prevalence of CKD is increasing worldwide, likely driven by an aging population.8
Worldwide death rates attributable to CKD have also risen dramatically, with a median
increase of 36.9% from 1990 to 2013.43 In addition to heightened mortality risk, older adults
with CKD are also more likely to suffer disability from physical and cognitive dysfunction.5
However, determinants of CKD are poorly understood in the aging population of developing
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countries, including those in Central America. In this study, we explored traditional and
novel risk factors for CKD in a nationally representative sample of elderly Costa Ricans. We
have identified that the prevalence of CKD among older Costa Ricans is 20%, similar to the
CKD prevalence previously described among older adults in the US.9 Our study also found
that the prevalence of CKD among older Costa Rican women is higher than among older
Costa Rican men. Previous studies have highlighted that women in Costa Rica have higher
burdens of hypertension, diabetes, and obesity.44 Consistent with these reports, our study
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showed that after adjustment for comorbidities and SES, the association of female gender
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and CKD was no longer statistically significant. Also, while wealth and education disparities
are also known to drive differential risk for chronic disease states including
CKD,10,16,32,33,45 our study did not find wealth or education gradients with CKD among
elderly Costa Ricans. This may be explained by the fact that while most of the subjects had
low educational attainment, the vast majority also had recent access to medical care. Indeed,
nephrologic clinical services have been freely accessible in Costa Rica since 1968, as part of
the national social security system that ensures that citizens have free access to medical
attention as needed.46 Therefore, the lack of socioeconomic gradients in CKD may represent
a success in Costa Rica’s adoption of widespread health care coverage.18
Our study also highlighted a potential relationship between altitude of residence and risk of
CKD. The association between altitude and CKD risk remained robust after adjustment for
age, comorbidities, region, wealth, education, and access to recent medical care. Living at
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high altitudes is a known risk factor for high altitude renal syndrome (HARS), a syndrome
resulting from chronic hypoxia that is characterized by polycy-themia, hyperuricemia,
hypertension, and proteinuria.30,47,48 However, this syndrome has generally been described
at altitudes hgher than 2400 meters above sea level, and most Costa Ricans live either at sea
level or in the Central Valley, about 1,200 meters above sea level. It is possible that the
direct renal injury or reduction in renal plasma flow observed in HARS is present to a lesser
degree at the highest altitudes in Costa Rica, and that older adults are particularly susceptible
to these exposures. However, further studies are needed to understand possible factors
related to higher altitude that may explain the patterns observed in this study.
This study also identified Guanacaste and Limon provinces as the regions in Costa Rica with
the highest prevalence rates of CKD. A recent study of Costa Rican death records over the
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last 40 years noted that Guanacaste province had the most marked rise in age-adjusted CKD
mortality.19 These findings in aggregate warrant future studies to further investigate risk
factors specific to these regions, including factors that may distinguish Guanacaste and
Limon from Puntarenas, the other low-altitude coastal province in Costa Rica. In terms of
putative differences in environmental exposures, residents of the low-altitude provinces
typically encounter warmer weather than the central provinces (Figure 1) and rely
predominantly on agriculture for commerce than residents of the Central Valley. The
agricultural products of these regions are distinct: according to the 2014 agricultural census,
the main crops in Guanacaste are beef, sugar cane, and rice, whereas in Limon, bananas and
other fruits are the predominant export items.31 Guanacaste and Limon have also attracted
the highest proportions of immigrants from other Central American countries, including
Nicaragua, where the epidemic of CKDnT has been extensively documented.29,49,50 While
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the causes of CKDnT are unknown,50 hypotheses include heat stress caused by year-round
extreme high temperatures and humidity, heavy agricultural work and toxic pesticides.
These factors are thought to predispose certain individuals to recurrent volume depletion,
resulting in activation of both intra- and extra-renal pathways that drive renal injury.52
However, while CKDnT have been characterized as a tubulointerstitial nephropathy with
low-grade proteinuria,24,51 previous reports of kidney biopsies performed among Costa
Ricans with CKD have identified focal and segmental glomeruloscerosis, membranous
nephropathy, mesangial proliferative glomerulonephritis and crescent glomerulonephritis as
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the most common findings.46 Future studies, ideally including data on environmental
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exposures and kidney biopsies, will be important to elucidate the nature of CKD found
among populations living in different regions of Costa Rica.
Study limitations
Our study has several limitations that must be acknowledged. As some of our data is cross-
sectional, we cannot make inferences on causality. Also, while we attempted to remain as
consistent as possible to the 2012 Clinical Practice Guidelines from the KDIGO working
group recommendations on the diagnosis of CKD,40 we did not have data on proteinuria that
is necessary to characterize early CKD (e.g., stage 2, eGFR between 60 and 90 ml/min).
Therefore, we chose to categorize subjects as having CKD only at later stages (i.e., 3a and
beyond), as proteinuria is not a necessary component for diagnosis at later stages of renal
dysfunction, and the CKD-EPI formula is more precise.40 Additionally, there is an active
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The health consequences of CKD for older adults include higher risk of morbidity and
mortality, even at higher levels of eGFR.5,12 Therefore we chose to include mild reductions
in eGFR (corresponding to CKD stage 3a) in our estimates. CRELES investigators did not
perform serial measurements of eGFR during the first wave of surveys. Therefore, as the
classification of CKD requires two eGFR measurements at least 90 days apart,40 we
completed a sensitivity analysis including data from the second survey wave, completed two
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years after the initial wave. The resulting longitudinal random effects models confirmed the
significant associations we observed between province, altitude, and CKD in Costa Rica.
Conclusion
In Central American and other developing countries, where data are most scarce on the
epidemiology of CKD, studies are urgently needed to explain the rising prevalence of CKD
and precipitous rise in CKD-related deaths. While we did not identify socioeconomic
disparities in CKD risk among elderly Costa Ricans, our findings of potential geographic
and regional determinants of CKD in Costa Rica provide a platform for further
investigation.
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Acknowledgments
The CRELES study was funded by grants from the Wellcome Trust; the National Heart, Lung, And Blood Institute
and the National Institute of Diabetes and Digestive and Kidney Diseases of the United States National Institutes of
Health. The content is solely the responsibility of the authors and does not necessarily represent the official views
of the National Institutes of Health or Wellcome Trust.
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Figure 1.
Map of Costa Rica with regional prevalence, annual heat exposure, and altitude
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Figure 2.
Prevalence of CKD by age and sex (smoothed with locally weighted polynomials)
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Figure 3.
Probability of CKD by altitude of residence, adjusted for age, gender, comorbidities, and
Province of residence
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Table 1
Percent visited physician in last 12 months (n=2,380) 86.8 [84.7,88.6] 95.2 [92.7,96.9] < 0.0001
Mean wealth proxy / scale of goods 8.2 [8.1–8.3] 8.2 [8.1–8.4] 0.66
Mean altitude of home above sea level, m 795 [767–824] 931 [882–979] < 0.001
Percent rural residence (n=981) 35.3 [32.8,37.9] 32 [27.9,36.3] 0.20
Province of Residence, % < 0.001
San Jose (n=928) 35.7 [33.1,38.3] 36.3 [31.9,40.9]
Alajuela (n=425) 16.6 [14.7,18.7] 10.3 [8.1,13.1]
Cartago (n=413) 13.9 [12.2,15.9] 23 [19.2,27.4]
Heredia (n=188) 8.3 [6.8,10.0] 7.7 [5.3,11.1]
Guanacaste (n=275) 9.5 [8.0,11.2] 8.8 [6.6,11.7]
Puntarenas (n=254) 9.8 [8.3,11.5] 6.3 [4.7,8.5]
Limon (n=174) 6.3 [5.1,7.8] 7.5 [5.6,10.1]
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Percent current smoker (n=211) 11.2 [9.5,13.2] 5.1 [3.3,7.7] < 0.001
Mean HbA1C, % 5.7 [5.7–5.8] 5.9 [5.8–6.0] 0.008
Percent with HbA1C ≥ 6.5% (n=350) 13.3 [11.6,15.3] 17 [13.6,21.0] 0.07
Mean systolic blood pressure, mmHg 143.4 [142.2–144.6] 147.0 [144.7–149.3] 0.006
Mean diastolic blood pressure, mmHg 83.9 [83.3–84.5] 83.5 [82.2–84.8] 0.49
Percent with measured hypertension (>150/90) (n=1212) 42.2 [39.5,44.9] 50.5 [45.8,55.1] 0.002
Percent BMI > 30 kg/m2 (n=593) 27.4 [24.9,29.9] 26.4 [22.3,30.9] 0.70
Percent taking medication for:
Diabetes (n=424) 16.3 [14.4,18.4] 23.3 [19.4,27.7] 0.002
Hypertension (n=1,210) 39.5 [36.9,42.2] 61.2 [56.5,65.6] < 0.0001
Hyperlipidemia (n=498) 18.8 [16.8,21.0] 30.7 [26.3,35.4] < 0.001
Continuous variables are reported as means, and categorical variables as percentages, with 95% confidence intervals in bracket.
The reported sample sizes (n) for categorical variables are the number of survey participants within each category.
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Table 2
Etiologic model of CKD in Costa Rica: regional and traditional risk factors
Province of Residence*
Alajuela 1.01 [0.69,1.49] 0.95 1.02 [0.69,1.51] 0.93
Cartago 1.37 [0.97,1.94] 0.07 1.37 [0.96,1.95] 0.09
Heredia 0.93 [0.55,1.58] 0.79 0.84 [0.51,1.41] 0.51
Guanacaste 3.43 [1.84,6.38] <0.001 3.65 [1.91,6.97] <0.001
Puntarenas 1.99 [1.14,3.48] 0.02 2.14 [1.19,3.83] 0.01
Limon 4.84 [2.56,9.15] <0.001 4.53 [2.35,8.76] <0.001
Education (per 1-year increase) 1.00 [0.97,1.03] 0.84
Recent MD Visit 1.64 [0.94,2.87] 0.08
Current smoker 0.65 [0.36,1.16] 0.15
Diagnosed with DM 0.63 [0.39,1.03] 0.07
Diagnosed with HTN 1.25 [0.87,1.80] 0.22
HbA1C % (per 1-% increase) 1.11 [0.95,1.29] 0.18
HbA1C% > 6.5 0.89 [0.47,1.71] 0.74
Systolic Blood Pressure (per 1-mmHg increase) 0.99 [0.99,1.00] 0.08
BP >150/90 1.60 [1.10,2.32] 0.01
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BMI> 30 kg/m2 0.93 [0.69,1.25] 0.64
Prescribed Medication for:
DM 1.73 [1.04,2.87] 0.04
HTN 1.52 [1.06,2.18] 0.02
Hyperlipidemia 1.48 [1.10,1.99] 0.01
Abbreviations: aOR=adjusted Odds Ratio, CI=confidence interval, CKD=chronic kidney disease, SES=socioeconomic status, m=meter, MD=medical doctor, DM=diabetes mellitus, HTN=hypertension,
HbA1C=glycosylated hemoglobin, mmHg=millimeter mercury, BP=blood pressure, BMI=body mass index
*
Reference: San Jose
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Table 3
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Appendix 1
Province of Residence*
Alajuela 0.92 [0.61,1.37] 0.67 0.95 [0.64,1.43] 0.82
Cartago 1.22 [0.86,1.72] 0.27 1.29 [0.91,1.83] 0.15
Heredia 1.49 [0.97,2.30] 0.07 1.31 [0.85,2.01] 0.22
Guanacaste 2.33 [1.27,4.28] 0.01 2.66 [1.45,4.89] 0.00
Puntarenas 1.22 [0.68,2.19] 0.50 1.38 [0.77,2.48] 0.28
Limon 2.95 [1.53,5.68] <0.001 2.72 [1.41,5.25] <0.001
Years of Education 1.02 [0.99,1.05] 0.24
No Insurance 0.91 [0.67,1.24] 0.57
Recent MD Visit 1.07 [0.72,1.61] 0.73
Current smoker 0.6 [0.38,0.95] 0.03
Diagnosed with DM 0.71 [0.44,1.16] 0.18
Diagnosed with HTN 1.8 [1.31,2.48] <0.001
HbA1C % 1.1 [0.96,1.26] 0.17
HbA1C % > 6.5 1.88 [1.24,2.86] 0.00
Systolic BP (per mmHg rise) 0.99 [0.98,1.00] 0.01
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BP > 150/90 1.3 [0.96,1.76] 0.09
BMI > 30 kg/m2 0.97 [0.75,1.25] 0.81
DM 1.29 [0.78,2.14] 0.32
HTN 1.6 [1.18,2.16] <0.001
Hyperlipidemia 1.53 [1.20,1.96] <0.001
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