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Chronic kidney disease
Chronic kidney disease mortality trends in selected Central America countries, 1997–2013: clues to an epidemic of chronic interstitial nephritis of agricultural communities
  1. Pedro Ordunez1,
  2. F Javier Nieto2,
  3. Ramon Martinez1,
  4. Patricia Soliz1,
  5. Gloria P Giraldo1,
  6. Susan Anne Mott3,
  7. Wendy E Hoy3
  1. 1 Pan American Health Organization, Washington, District of Columbia, USA
  2. 2 College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon, USA
  3. 3 Centre for Chronic Disease and CKD. CRE, UQCCR, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
  1. Correspondence to Dr Pedro Ordunez, Department of Non Communicable Diseases and Mental Health, Pan American Health Organization, NW, Washington, D.C. 20037, USA; ordunezp{at}paho.org

Abstract

Background In Central America, chronic interstitial nephritis of agricultural communities (CINAC) has reached epidemic proportions. Clusters of cases have been described in several farming communities. Its aetiology remains uncertain and a controversy exists on its key triggers, among them the heat stress–dehydration mechanism and the toxic exposure to agrochemicals.

Methods This study analysed the mortality pattern and trend of chronic kidney disease code N18 (CKD-N18) according to the International Statistical Classification of Diseases and Related Health Problems-10th Revision, the proxy and the underlying cause of death, in four selected Central American countries from 1997 to 2013. In addition, we used exponential regression to retrospectively model the likely onset and prior trajectory of the epidemic.

Results Between 1997 and 2013, CKD-N18 mortality accounting 47 885 deaths (31% were female), 19 533 of which occurred below 60 years of age (26% female). The excess of mortality starts as early as 10–14 years of age for both boys and girls. El Salvador and Nicaragua, with mortality rates between 9-fold and 12-fold higher than reference countries, were the most affected. Statistical modelling suggests that the epidemic commenced around the mid-1970s, coinciding with important changes in modes of agricultural production.

Conclusions This study provides the most comprehensive mortality analysis of this epidemic published to date and confirms an excess of CKD-N18 mortality and its relation with the epidemic of CINAC. The overall trends and the mortality pattern among women, children and adolescents suggest that the heat stress–dehydration hypothesis cannot fully explain this epidemic and that other environmental factors, more likely agricultural practices and agrochemicals, may be causally involved.

  • chronic di
  • epidemiology of chronic non communicable diseases
  • public health
  • mortality
  • social inequalities

https://doi.org/10.1136/jech-2017-210023

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    Introduction

    In Central America, a form of chronic kidney disease (CKD) has reached epidemic proportions.1 Numerous cases have been described in clusters of socially vulnerable farming communities mainly in Nicaragua2 3 and El Salvador.4 One example is La Isla, a small sugarcane community in Nicaragua, where CKD has caused the deaths of so many young men that it has become known as the ‘Island of Widows’.5 The total burden to health systems is enormous; the main health facility of south-eastern El Salvador, San Miguel Hospital, is filled with young patients requiring access to dialysis.1 Cases are predominantly young men, but there are many cases among women.2 4 6 The disease has been reported among sugar cane cutters,7 8 but other non-agricultural workers have also been affected.4 6 9 10

    The clinical features of the disease are consistent with those of a chronic interstitial nephritis. Patients have few early symptoms and very low levels of proteinuria and often present at an advanced stage of renal disease.9 Its morphological pattern has been described primarily as chronic tubule-interstitial nephritis,11 which is consistent with its early clinical presentation; additionally, chronic glomerular damage has been reported.12 There is rarely a history of diabetes and hypertension, or other known renal syndromes, particularly in patients below 60 years of age.9 10 13 It may progress to end-stage renal disease where patients require dialysis. CKD with similar characteristics has been widely documented in agricultural communities in other parts of the world, mainly in Sri Lanka and India.10 12–14 After recognising that many commonalities exist between the epidemics of CKD, researchers proposed the term ‘chronic interstitial nephritis of agricultural communities (CINAC)’,10 a term that better synthesised its main epidemiological, clinical and pathological characteristics, and that we will use herein. However, other names used are CKD of non-traditional causes (CKDnT),1 CKD of unknown causes2 and Mesoamerican nephropathy8 among others.

    The aetiology of CINAC and the determinants of the epidemic remain controversial. However, there is considerable evidence supporting a multifactorial origin, in a context of social vulnerability and precarious living and working conditions. Heat stress–dehydration mechanism is a lead hypothetical mechanism under discussion, particularly to explain the cases among sugar cane cutters.15 16 However, toxic exposure to agrochemicals has also been posited as an additional possible causative factor.10 13 17

    The availability of updated CKD mortality data as well as the recent epidemiological, clinical and pathological evidence on CINAC, particularly in women, children and adolescents,6 18–20 justifies additional study. Accordingly, the aim of this new study is to expand mortality analyses conducted previously21 22 to cover a longer period of time and capture more cases, with particular attention to women and adolescents and children, and to better characterise the pattern of this CKD epidemic. An additional aim is to estimate the time of onset of the epidemic. Hence, this new study may provide insights regarding the dynamics and origins of the current epidemic.

    Methods

    The study focuses on mortality from ‘chronic kidney disease’ as an underlying cause of death code N18 (CKD-N18) according to the International Statistical Classification of Diseases and Related Health Problems-10th Revision (ICD-10).23 Indeed, most of the CKD deaths (codes N17-19) are coded as CKD-N18.1 It has also been previously used by Pan American Health Organization (PAHO)21 and others24 as proxy for mortality attributed to CINAC in Central America. All registered CKD-N18 deaths occurring in selected countries with medium-quality data according to WHO criteria (70%–90% completeness of estimated deaths and 10%–20% of ill-defined causes of registered deaths)1 and a high level of data availability—Costa Rica, El Salvador, Nicaragua and Panamá—from 1997 to 2013, are the subject of the analyses. Belize, Guatemala and Honduras were excluded due to lack of data for the study period. Cuba and the USA were used as reference because of high quality of data and availability and because they have the lowest levels and the most stable trends of CKD-N18 mortality in the Americas.21 22 Absolute numbers of deaths, age–sex specific death rates and age-standardised mortality rates were selected as mortality measurements.

    Data sources

    The regional mortality database of the PAHO25 was used to tabulate the number of deaths by country, year, age group, sex and underlying causes of death. Population estimates by country, year, sex and age group were from World Population Prospects, 2015 revision.26 Premature mortality was defined as the mortality occurring below 60 years of age. This cut point was used because CKD is very infrequent in persons below 60 years of age; specifically, CKD attributed to diabetes or hypertension, the main causes of CKD worldwide, in addition to ageing.

    Statistical methods

    WHO/PAHO recommended methods for correcting incompleteness and inadequacies in recorded deaths from the national vital statistics systems were used and are described elsewhere.27 28 The estimates of the central death rates (nMx) for the corresponding age groups and sex are obtained from life tables from the Global Burden of Disease Study 2013.29 All corrected deaths with underlying cause of death coded as CKD-N18 were tabulated by country, year, sex and 5-year age groups (from 0 to 4 to 90–94 and 95+) from 1997 to 2013 or last available year. Age-specific mortality rates per 100 000 population were computed for deaths coded as CKD-N18 by country, year, age group and sex. Age-standardised mortality rates were obtained by the direct method of adjustment using the 2000–2015 WHO world standard population.30

    The average annual percent change (AAPC) of age-standardised mortality rate was calculated by regressing natural logarithmic death rate on year, using ordinary least squares regression (exponential regression model) (ln(rate)=α+β×year). The AAPC in rates was derived from the coefficient (β) for each country (overall and stratified by sex), for the whole period (1997–2013) using the formula AAPC=(EXP (β)−1)×100.

    To estimate the time of onset of the epidemic, linear and exponential regression models were computed and fitted to the time series of age-standardised mortality rates for CKD (dependent variable) by country and sex, against year of occurrence of death (independent variable). The exponential model was selected as it better fitted the data with lower mean squared error and SE than the linear model. As the reference threshold value to approximately determine the starting year of the CINAC epidemic in El Salvador and Nicaragua, we used data from Cuba because of the geographical and climatic similarities with the countries of interest. Thus, we used an age-standardised mortality rate of 1.5 per 100 000 population, which is twofold the corresponding rate in Cuba for the whole period 1997–2013.

    Results

    Between 1997 and 2013 in countries selected for this analysis, mortality rates due to CKD-N18 were notably higher than in USA and Cuba, accounting for an estimated total of 47 885 deaths (31% female), and 19 533 of which occurred before 60 years of age (26% female). In El Salvador, mortality increased from 18.7 deaths per 100 000 in 1997 to 47.4 deaths per 100 000 in 2012 (last available year), an AAPC of 17.6%. In Nicaragua, mortality increased from 23.9 in 1997 to 36.7 deaths per 100 000 in 2013, with an AAPC of 9.7% (table 1).

    View this table:
    Table 1

    Chronic kidney disease deaths, numbers, age-standardised mortality rates and average annual percent change, in all ages population, by time period, for selected Central American countries, Cuba and the USA

    Although men show disproportionately higher levels of mortality, women in El Salvador y Nicaragua also show notably higher levels of mortality compared with their counterparts in USA and Cuba. The notorious differences between the steeply rising mortality curves in Nicaragua and El Salvador and the almost flat lines of Costa Rica and Panama are evident (figure 1).

    Figure 1
    Figure 1

    Chronic kidney disease age-standardised mortality rate trends in all ages population, by sex and selected Central American country, 1995–2013.

    Male and female premature mortality rates in selected countries are higher than those of Cuba and USA at every age group below 60 years of age, and the male rates clearly exceed female rates (figure 2A). Furthermore, data show that such excess of risk begins to appear as early as 10–14, and it is very evident as 15–19 years of age, for both boys and girls. The mortality for adolescent and young adult males over the age of 14 years grows exponentially, particularly in Nicaragua and El Salvador, far exceeding all other studied countries (figure 2B).

    Figure 2
    Figure 2

    Chronic kidney disease premature mortality rates, by sex and age group for selected Central American counties, Cuba and USA, 2010–2012. (A) 0–59 years, by 5 year age group. (B) 0–29 years, by 5 year age group.

    Regression models of the population below 60 years of age provided backwards estimates of the epidemic progression shown in figure 3. This model suggests that the epidemic of CINAC in El Salvador and Nicaragua could have commenced around the mid-1970s.

    Figure 3
    Figure 3

    Chronic kidney disease age-standardised mortality rates, including projections, in below 60-year-old population, by sex for El Salvador and Nicaragua, 1975–2013.

    Discussion

    Earlier exploratory analysis showed that the pattern of mortality below 60 years of age due CKD-N18 in men during 2000–2010 coincided with reports of a severe form of CKDnT in El Salvador and Nicaragua.21 Another report22 demonstrated that, even though the CKD-N18 mortality rates were higher in men, women had also substantially higher mortality than women in the reference countries, as well as an excess mortality in young adults, particularly in the most affected countries. These early analyses21 22 were restricted to the 2000–2010 period, at a time when the clinical and epidemiological research, particularly in women, children and adolescent, was very limited.

    By adding six additional years of data and thousands of deaths, our study provides an updated and more complete view of the epidemic. Our results confirm a clear pattern of elevated CKD-N18 premature mortality in El Salvador and Nicaragua, consistent with numerous case reports of CINAC in agricultural workers of those countries.2–10 These farm workers are largely employed in strenuous, repetitive work in hot and humid conditions, and operate in an unregulated and hazardous working environment. Both men and women in these communities are generally poor, malnourished, poorly educated and do piece work in the unofficial economy without job security or benefits. Remuneration is based on daily output, encouraging maximal exertion, particularly in sugar cane cutters.7 8 15 16 Based on these observations, a number of authors have suggested the heat stress–dehydration mechanism as the main determinant of this epidemic.7 8 15 16

    However, our results show that CKD-N18 high mortality rates observed among women, who are less represented among agricultural workers, living in clusters of farming communities,4 6 challenge the explanation that heat stress–dehydration is the primary factor to explain the epidemic. A plausible complementary explanation is that women living in farming communities are exposed to varying levels of environmental pollutants, even when not directly working in agriculture or working in other roles. A recent USA study of 32 000 wives of pesticide applicators, who had never applied pesticides themselves, showed their end-stage renal disease risk to be significantly correlated with their husbands’ cumulative pesticide exposure, suggesting that exposures to spray drift carried by their husbands may be involved.31 The mortality pattern observed in our study and concurrent research findings in this context suggest an exposure gradient or a dose–response effect that may explain disparities by sex in the case of the CINAC epidemic.

    Another important observation is the mortality pattern observed in selected countries compared with Cuba and USA on very young adults (below age 30 years) and even as early as age 10–14 years in both sexes. These findings are consistent with reports that almost half the children in the Pediatric Central Renal Disease Center in Guatemala poorly defined kidney disease are largely referred from regions where CINAC has been reported in adults.18 Moreover, children and adolescents in Nicaragua and El Salvador where CINAC is common in adults tend to have elevated levels of markers of renal damage,19 specifically including markers of tubular injury in Nicaragua.20 Furthermore, despite some progress, there are reports of child labour in vulnerable communities affected by CINAC.32 Indeed, a study conducted in Nicaragua among children aged 5–14 years from 1995 to 2006 reported 2069 acute pesticide poisoning cases, and among them, 432 were occupational.33 Combined with these observations, the excess mortality among children and adolescents strongly suggests the possibility of early and long-term exposure to environmental factors, most likely toxics, might be infectious or both, under a likely background of impaired renal development,1 compounded by social vulnerability, rather than heat stress–dehydration, as the lead culprit to explain the CINAC epidemic.

    Based on our statistical projections, we estimate that the onset of the epidemic of CINAC may have occurred around mid-1970s, a period which coincided with important changes in agricultural production in this region. The beginning of the epidemic (1975–1990) run in tandem with the growth of cotton cultivation in Nicaragua and El Salvador. In addition, sugar cane production grew 1.4-fold and 2.0-fold between 2000 and 2013 in Nicaragua and El Salvador, respectively. According to United Nations Food and Agriculture Organization,34 pesticide imports increased from $25 to $64 million and from $25 to $48 million in Nicaragua and El Salvador, respectively. In the same period, the total export values of agricultural products grew, from $69 to $240 million in Nicaragua and from $79 to $170 million in El Salvador.

    Several authors have been extensively documented occupational and environmental hazards in Central America. These may include import and use of unregulated agrochemical products, excessive and escalating applications, and inappropriate methods of product dispersal, which widely contaminate non-crop areas, soil, waterways and air, with insufficient, absent or not enforced labour and occupational safety regulations.35–37

    It is important to point out that the toxic and the heat dehydration hypotheses are not incompatible, but rather complementary. Taken together, the existing evidence points to the biological plausibility of synergism, that is, a more comprehensive multideterminant model of causation, where organ damage results from multiple risk factors, acute and chronic, acting simultaneously or sequentially over the life course amplifying the effect of each other.1 In others words, in Central America, as in many others high-intensity agricultural areas, the work and temperature stresses and the contaminated environment might lead to an accelerated loss of nephrons and a relative depletion of kidney mass relatively early in life, after reaching working age, particularly among males. This might be exacerbated in especially vulnerable persons, for example, those with nutritional deficiency.

    However, the primary histopathology of CINAC is not glomerular but rather a tubule-interstitial pattern, seemingly associated with oxidative stress. With its very high oxygen needs and metabolic activity, the tubulointerstitial compartment of the kidney could exhaust prematurely if not adequately fuelled and/or partially poisoned. Hence, when exposure to agrochemicals or other toxicants is combined with dehydration, it could result on increased concentration of these toxics and multiply their nephrotoxic effects. Indeed, the combination of hot temperature with misuse of agrochemicals has been linked to the epidemic in El Salvador and Sri Lanka.10 17 38 39

    Further analysis is needed to understand why the frequency of CINAC as well as the CKD-N18 mortality is higher in Nicaragua and El Salvador than in other Central American countries despite their many similarities in terms of geographical, economic, cultural, epidemiological characteristics and agricultural production. For instance, Costa Rica has high CKD-N18 mortality,23although a very different pattern to that observed in El Salvador and Nicaragua, a fact which might be attributed in part to its level of economic development, percentage of rural population and land dedicated to agriculture, access and quality of care, and because many agricultural workers are migrants from Nicaragua where they live and where they finally return to die. However, mortality data from Guanacaste (a Costa Rican province which borders with Nicaragua and is an important agricultural zone) show a very similar pattern to that observed in El Salvador and Nicaragua, that is, starting in the mid-1970s, mortality increased at very young age and among women.23 In addition, the case of Cuba, a hot and humid tropical country with a long tradition of sugar cane production and low levels of CKD mortality, deserves further study. Cuba has gradually mechanised sugar cultivation, and its occupational health regulations seem more stringent; and the use of agrochemicals has been highly restricted for decades due to economic circumstances and to national environmental protection policies.40 These observations emphasise the need for further research to explain the mosaic pattern of geographical distribution of CINAC in Central America, a pattern that does not provide strong support for the heat stress–dehydration hypothesis.

    Limitations of the study include the use of CKD-N18, as an underlying cause of death, is required. However, data available for this study, although with medium quality, are not enough to enable analysis of both underlying and associated causes of death using ICD-10. Additionally, data are limited to national level, impeding subnational analyses to compare urban and rural areas, in burden of disease and trends in mortality. However, cases of CINAC seem to be very predominant in clusters of farming communities. The number of cases could be over-reported in a context of increased public awareness about the epidemic itself. However, the striking differences between the most affected countries and the rest of Central America and reference countries cannot be solely explained by a drift on physicians certifying CKD as the ‘underlying’ cause of death. In addition, the observed excess CKD-N18 mortality in Nicaragua and El Salvador cannot be explained by obesity and diabetes’ prevalence and trends because they show similar patterns in all studied countries.41 Finally, although selected countries for this study share many similarities in their agricultural pattern, evidence is very limited in terms of differences between countries in agricultural, environmental protection or employment practices that might explain the differences observed.

    In conclusion, even though this study has limited capacity to explain causation, it provides the most extensive mortality analysis to date, confirming previous observations of an excess of CKD-18 mortality and its relation with the epidemic of CINAC. The mortality pattern among women, children and adolescents confirmed in this study, combined with new epidemiological, histopathological and clinical evidence, suggests that there are additional factors, beyond the heat stress–dehydration hypothesised mechanism, that are linked to the broader environmental context surrounding this epidemic. Our results add urgency to earlier calls for further examination of the role of agricultural practices and agrochemicals in the causal pathway of this epidemic, including the need of qualitative research enable to explain the exposure and consequent health risks for women and other persons not directly exposed to pesticides. In addition to the need to elucidate causation, comprehensive multilevel policy interventions must take place to address evident modifiable risk factors to avert the continuation of this tragic epidemic, its detrimental economic consequences and the unnecessary human suffering.

    What is already known on this subject

    • In Central America, mainly in Nicaragua and El Salvador, a form of chronic interstitial nephritis of uncertain aetiology has reached epidemic proportions affecting vulnerable farming communities and young male agricultural workers.

    • A controversy exists on its key triggers, among them the heat stress–dehydration mechanism and the toxic exposure to agrochemicals.

    • The availability of updated mortality data as well as new epidemiological, clinical and pathological evidence, particularly in women, children and adolescents, justifies a new mortality analysis, as well as to estimate its onset to further understand the context.

    What this study adds

    • This study provides the most comprehensive mortality analysis of this epidemic published to date and confirms the previous observation of an excess of chronic kidney disease code N18 mortality and its relation with this epidemic.

    • The mortality pattern among women, children and adolescents suggests that there are additional factors, beyond the hypothesised heat stress–dehydration mechanism, which point to the broader environmental context surrounding this epidemic.

    • These new clues need to be further examined to understand the role of agricultural practices and agrochemicals in the causal pathway of this epidemic, even amidst resource constraints.

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    Footnotes

    • Contributors PO, WEH, RM: research idea, study design, analysis; PO, WEH, RM, FJN, PS, GPG, SAM: interpretation of findings and MS preparation. Each author contributed important intellectual content during MS drafting and revision and accepts accountability for the overall work.

    • Disclaimer The findings and conclusions in this report are solely responsibility of the authors and do not necessarily represent the official position of the Pan American Health Organization or any of the authors’ affiliated institutions.

    • Competing interests None declared.

    • Provenance and peer review Commissioned; externally peer reviewed.