The Central American Epidemic of CKD

Epidemiology and Manifestations of Central American CKD

Based on several unpublished and published prevalence studies, review of clinical charts, and discussions with local physicians, it seems that the regional epidemic of CKD has several distinguishing characteristics: (1) although the apparent excess of CKD seems to extend across Central America, it is concentrated along the lowland areas of the Pacific coast; (2) men seem to be disproportionately affected, with creatinine elevations often noted in the third or fourth decade of life; and (3) significant proteinuria is uncommon, with a clinical profile most consistent with nonglomerular disease resulting in small echogenic kidneys on ultrasound imaging (Table 1) (2,3,6–14). Additionally, a symptom complex referred to as chistata is common among individuals in this region. Chistata is a colloquial term used to characterize a constellation of symptoms, including lower urinary tract discomfort and urinary urgency, that approximate the clinical term dysuria. The etiology of chistata remains uncertain, although it is unlikely infectious (3), and whether chistata is associated with CKD remains unknown. Overall, the regional epidemic of CKD remains insufficiently studied, with no direct ascertainment of kidney function or creatinine clearance and no kidney biopsies in individuals with early stages of CKD.

The limited published community- and population-based literature on the epidemic of CKD in this region has focused on the prevalence of reduced GFR by sex, occupation, altitude, and location, with some mention of heat stress (Table 2). For example, in Quezalguaque, a relatively low-lying community in northwest Nicaragua where residents are predominantly engaged in agricultural work, the prevalence of estimated GFR (eGFR) below 60 ml/min per 1.73 m² was 20% among men and 8% among women; this difference was most notable among men between 30 and 42 years, with 13.4% of men having an eGFR below 60 ml/min per 1.73 m² (4.9% of these men had a GFR below 30 ml/min per 1.73 m²) versus 3.3% (0%) of women (11). Furthermore, residents who lived at an altitude of <500 m above sea level were almost two times as likely to have an eGFR below 60 ml/min per 1.73 m² compared with those individuals who lived at a higher altitude. The results also suggested a possible association with occupational factors, such as past work in cotton or sugarcane, or exposure to pesticides. In contrast, in an inland high-altitude (∼1000 m above sea level) village near Matagalpa, Nicaragua, where the primary industry is coffee production, few, if any, individuals below 40 years old had an eGFR less than 60 ml/min per 1.73 m² (15). Although there was no statistically significant association between prior work in the sugar or cotton industries and low eGFR in the Quezalguaque study, relatively low numbers and survival bias may have limited the ability to appreciate a significant association. Taken in sum, these two studies suggest that altitude may be a critical factor; whether this factor reflects temperature variation, different environmental conditions and exposures, or different work and social practices cannot be determined from these studies.

Two other moderately sized surveys have explored this issue in greater detail. In the first study, Torres et al. (13) sampled 1096 residents between 20 and 60 years who were involved in different industries in northwest Nicaragua: mining/subsistence farming (100–300 m above sea level), banana/sugarcane production (100–300 m), fishing (0–100 m), services (0–100 m), and coffee production (200–675 m). The work by Torres et al. (13) noted that eGFR was less than 60 ml/min per 1.73 m² in 14% of men versus 3% of women and that lower eGFR was more common in the lower-altitude, high-work intensity regions, specifically those areas engaged in mining/subsistence farming and banana/sugarcane production. The prevalence of albuminuria was uniformly low across communities, and interestingly, 28% of men, most notably those men engaged in mining/subsistence farming, banana/sugarcane, and services, stated that they had been previously diagnosed with a urinary tract infection.

In the second study, Peraza et al. (12) sampled 664 residents between 20 and 60 years from five geographically varied communities in El Salvador who were involved in different industries: two sugarcane area (both 0–50 m above sea level), one sugarcane area (>500 m), one coffee production area (1650 m), and one services area (650 m) (12). In the two low-lying sugarcane communities, 19% of men had an eGFR less than 60 ml/min per 1.73 m² versus 2% in the high-altitude sugarcane community. Furthermore, age-adjusted duration of work in low-lying sugarcane communities was independently associated with a higher likelihood of reduced kidney function. Critically, both work tasks and agrichemical use in the sugarcane communities were similar regardless of altitude, with the major difference among the sugarcane communities being an average temperature that was 4^◦C lower in the community at high altitude. This work expanded on prior observations from a referral hospital in El Salvador. In this cohort comprised of 205 individuals initiating dialysis from November of 1999 to March of 2000, two-thirds lacked traditional kidney failure risk factors; these individuals were predominantly male farmers residing in coastal areas or close proximity to rivers, with previous exposure to insecticides and pesticides (9).

Potential Causes

There are multiple theories for the apparent excess of kidney disease in this region, and many of these theories are summarized in refs. 2 and 14. Hypotheses include heat stress, agrichemicals, heavy metals, aristolochic acid, medications and other toxins, including contaminants in locally distilled alcohols, infections such as leptospirosis, and genetic and developmental susceptibility factors. Very few kidney biopsies have been performed, particularly in earlier stages of disease, providing no histologic clues to etiology. The limited evidence available to date supporting and opposing several of these hypotheses is reviewed in Table 3. Critically, other potential causes certainly exist, and, as evidenced by the chain of events that led to the recognition of aristolochic acid as a nephrotoxin (16), it is quite possible that the cause of kidney disease may not be among those causes listed in Table 3 or that several of these possibilities may be acting together to result in CKD.

Toxins, including heavy metals, pesticides and herbicides, are potential causes of kidney disease in the region, reflecting prior and perhaps current environmental conditions and agricultural practices (17). Critically, if toxins that are filtered by the kidneys, such as heavy metals, contaminate drinking water, kidney toxicity could result from even apparently low concentrations of these toxins in the water supply, making the interpretation of environmental testing results more challenging. A possible discrepancy between environmental toxin concentration and individual person exposure could reflect the extremely high water intake needed to replace volume losses, particularly among workers in very hot and humid conditions, which could result in significant kidney toxicity because of high net kidney exposure to potential environmental nephrotoxins as a function of total filtered load.

We find the hypothesis of heat stress, potentially superimposed on other factors, compelling and believe that it, in particular, requires additional investigation (18). Critical to this hypothesis is that CKD is occurring more often among individuals who have engaged in more strenuous physical activity in extreme environmental conditions. Sugarcane cutting is an exceptionally physically demanding task. On the night before harvesting, the cane field is burned, defoliating the field without damaging the cane stalk (Figure 1). The next morning, typically beginning before 6 a.m., cane cutters use machetes to harvest the cane as close to the base of the stalk as possible, with the average cutter harvesting between 5 and 7 tons of cane each day. The conditions can be oppressive, with a combination of very high temperatures, humidity, and solar radiation that sum to wet bulb globe temperatures above 30°C (with air temperatures often in the range of 38°C) by mid-morning in low-lying areas throughout the region (19,20). To place this information into context, the US Occupational Safety & Health Administration suggests that, for physically fit and temperature-acclimatized individuals wearing light summer clothing, each 15 minutes of heavy work in these conditions should be accompanied by 45 minutes rest to minimize the risk of exceeding a deep body temperature of 38°C (21).

Given the intensity of labor and the extreme conditions, the risk of heat stress and heat-related complications is high; accordingly, the risk of AKI would also be high. However, there are no published reports on the incidence of heat stroke in Nicaragua, although based on observations among workers and health care providers in the region, heat stroke does occur among workers, particularly earlier in the season when workers may not be acclimated. In observational studies in the general populations, including one study in Australia, heat waves are associated with increased likelihood of hospitalization for kidney-related disorders, including volume depletion and electrolyte abnormalities, with preexisting kidney disease an important risk modifier (22). Similar results have been seen during heat waves in California and Chicago, with AKI a more prominent cause of hospitalization during these episodes (23).

One major issue, particularly among workers engaged in strenuous physical activity, is volume depletion. Estimates from workers themselves in conjunction with observational reports suggest that anywhere from 5 to 15 L fluid intake is necessary to replace ongoing losses, with one small study interestingly showing that cane cutters who consumed more than 7 L water per day were more productive than those individuals consuming less water (24). Severe volume depletion can cause AKI in settings in which the degree of volume depletion exceeds the ability of counter-regulatory hormones to maintain end organ perfusion. The kidney is one of the most sensitive organs to acute changes in perfusion, and the risk of kidney ischemic injury may be particularly evident if the body’s ability to autoregulate glomerular filtration is impeded by agents like nonsteroidal anti-inflammatory drugs (NSAIDs) or if severe volume depletion occurs in the setting of other exogenous or endogenous nephrotoxins, such as muscle breakdown products that can be present in exertional rhabdomyolysis (25,26). Serum creatinine typically returns to premorbid levels after acute ischemic injuries, and in the absence of comorbid conditions or active medical monitoring, kidney injury may remain subclinical or unrecognized.

Key to this hypothesis is that subclinical or undiagnosed episodes of AKI are occurring in this region; however, data to either strongly support or refute this hypothesis are lacking. Assuming that subclinical insults do occur and that these insults are repeated over time, what will be the chronic effect of these repeated insults on the kidney? Recently, a new paradigm has been gaining favor that AKI, even with apparent recovery in kidney function, may not be innocuous (27). In this paradigm, either repair attempts themselves or ongoing insults with subsequent repair attempts lead to a self-perpetuating cycle of inflammation and repair, resulting in kidney fibrosis and clinically recognizable CKD. Accordingly, we hypothesize that repeated ischemic insults to the kidney caused by severe volume depletion with or without hyperthermia and potentially in conjunction with other kidney insults result in progressive kidney fibrosis and ultimately, kidney failure.

Why Now and Why Here?

There are several possible reasons why this epidemic is either occurring now or, if the substrate has been present for some time, being recognized now. First, most cases of CKD in Central America are indolent, because the tempo of disease is fairly slow with few clinical manifestations until overt kidney failure is present. In 1970, the average life expectancy in Nicaragua was 53 years, rising to 73 years in 2009 (28). This dramatic improvement is multifactorial, reflecting improved sanitation and availability of treatments for infectious diseases. Because people live longer, deaths caused by kidney disease have increased opportunity to manifest, with the nonspecific symptoms of uremia not being attributed other conditions. Second, Nicaragua and other Central American nations have increasingly available heath care. Although more elaborate care, including kidney replacement therapy, remains quite limited, increased awareness of chronic diseases and increased availability of simple serum creatinine tests mean that advanced CKD will less often go undiagnosed. Third, the world has become far less isolated, and reports of the unexpected are far more likely to be disseminated internationally. Based on discussions of CKD with Dr. Norman Jirón, one of the first practicing nephrologists in Nicaragua (D.R.B., personal communication), the prevalence of CKD in the northwest region of Nicaragua as far back as the 1970s seemed unusually high and manifested with many of the same features apparent in cases currently described, including young age of onset, male predominance, and employment in agrarian economic activity. Fourth, there may be new nephrotoxins present. Medications are widely available in Nicaragua without a prescription, and, for urinary syndromes, antibiotics are commonly prescribed, including intramuscular aminoglycosides (29). Additionally, NSAIDs are also widely used. One can envision the combination of aminoglycosides or NSAIDs with significant volume depletion enhancing the likelihood of developing AKI.

Implications and Future Directions

The epidemic of CKD in Nicaragua and elsewhere in Central America has important societal implications and potentially, worldwide relevance. Of note, there are several reports of multiple similar clusters of CKD worldwide; although many of these remain largely anecdotal, detailed descriptions exist for clusters in the Srikakulam District in Andhra Pradesh, India (30) and North Central Sri Lanka (31). In both of these settings, a tubulointerstitial pattern of kidney injury predominates, and, similar to northwestern Nicaragua and El Salvador, the climate is tropical, with many residents engaged in heavy, agricultural-based manual labor. In the coming years, as we confront global warming, population growth, and increased food and water scarcity (32), these extreme environments and working conditions may become more common, with CKD in Central America presaging a larger public health concern.

Ultimately, it is imperative that we gain a true understanding of the etiology of CKD in this region. In the coming years, we will continue to evaluate the epidemiology of CKD in Central America, assessing the presence of and predilection for CKD in various communities in this region, better defining the manifestations of CKD, and detailing the risk factors. In particular, we will evaluate the hypothesis that mild subclinical kidney injury can be induced by volume depletion in the extreme environmental conditions that are common in this region through novel use of AKI biomarkers in workers engaged in agricultural labor (33), with the overarching goal of preventing future cases of CKD.

Disclosures

None.