Introduction

Mesoamerican nephropathy (MeN) is a form of chronic kidney disease (CKD) of unknown etiology originally described in Central America, where this condition represents an important cause of morbidity and mortality (1). MeN is suspected to be a multifactorial disease, consequently, several inducing factors have been proposed; including heat stress (severe dehydration), excessive physical work (rhabdomyolysis), environmental toxins (agrochemicals, heavy metals, aristolochic acid), infections (leptospirosis, hantavirus), nephrotoxic drugs (NSAIDs) and genetic predisposition (familial nephropathy) (1-4). MeN has been documented mainly in workers who perform intense physical work in hot and humid conditions, and areas at lower altitudes (<500 m above sea level), such as sugar cane workers. This nephropathy is characterized by a tubular-interstitial CKD which generally presents anemia, low levels of serum electrolytes (hyponatraemia, hypokalemia, hypomagnesemia), hyperuricemia, aseptic dysuria (crystalluria with uric acid) and mildly altered urinalysis (1,3). This disease has also been found in other areas of the globe, geographically distant and ethnically diverse from Mesoamerica, such as Sri Lanka, Egypt, Udhanam (India), etc. Still, all of them had settings of hard physical work under high-heat climatic conditions as a common factor. Because of this, a more appropriate term for this condition has been proposed; CINAC (chronic interstitial nephritis in agricultural communities) (5-7). Since the Colombian Caribbean has agricultural communities, whose working conditions are like the ones found in areas where patients suffer from MeN, it was decided to explore whether this entity could also be found in this area. At the same time, it was decided to evaluate the degree of renal impact of a working day under conditions of physical and climatic demands.

Material and methods

A descriptive, observational, cross-sectional study was carried out, based on field work in a farm placed in an area with very hot weather (average 40°C), at 5 meters above sea level, in Sitio Nuevo (Magdalena, Colombia) and with a sample of 28 rural worker volunteers (rice fields).

Study participants consumed water ad livitum from study-instituted bottles. The amount consumed was measured and documented by study staff. The workers were evaluated twice during their working hours: 1) at approximately 6:00 AM before starting their work in the morning and 2) at approximately 5:00 PM at the end of the workday. The urine and blood samples were obtained in the field, and the latter were locally centrifuged. All the samples were stored in refrigerated containers (4°C) and soon transported to the central laboratory of Clínica de la Costa, in Barranquilla city (located 30 minutes away). The parameters measured were their weight, blood pressure, blood samples to measure hemogram, creatinine, urea, glucose, albumin, sodium, chloride, potassium, calcium, phosphorus, magnesium, uric acid and osmolarity, and spot urine sample to measure urine protein, and osmolarity. The clinical and biochemical data obtained for each individual was compared to see whether there was a significant difference between its morning and evening values. In those workers who developed acute kidney injury during the workday, defined as an increase of serum creatinine > 0.3 mg/dl between its morning creatinine and evening creatinine value, it was also compared for each obtained parameter if there was a significant difference between its morning and evening values.

The statistical analysis was performed applying Wilcoxon signed-rank test. This study was approved by Ethical Committee of Clínica de la Costa, Barranquilla (Colombia), and informed consent was obtained from all patients.

Results

Of the 28 young (x,SD: 25±5 years old) men workers (rice harvesters) evaluated, 5 (18%) presented a significant increase (>0.3 mg/dl) in serum creatinine during the workday (morning serum creatinine: 0.8±0.15 vs. evening serum creatinine: 1.2±0.17, p<0.001). The volume of water ingested by the workers was highly variable (2,861 ± 1,591 cc). There was no significant difference in the amount of hydration between the patients who experienced an AKI (change of ≥ 0.3 mg/dl in serum creatinine) during the workday and those who did not suffer it. Regarding the demographic characteristics of the evaluated individuals, they were of low socioeconomic status, working in agriculture since they were 18 years old, with no known medical comorbidities. They were exposed to agrochemicals and had eight hours workdays with programmed rest periods. In all the studied volunteers, it was compared for each obtained parameter if there was a significant difference between its morning and evening values. In this sense, statistically significant changes between morning and evening values were found only in six parameters: a significant increase in patients’ evening values of serum sodium, glucose, phosphorus, creatinine (they did not reach AKI criteria), urinary osmolarity, as well as a significant reduction in their serum potassium levels, compared to their morning values (Table 1).

Table 1: Modified parameters between morning and afternoon samples in all the studied workers (n = 28)

Note: BP: blood pressure.

Source: Own elaboration.

In those workers who developed AKI during the workday, it was compared for each obtained parameter if there was a significant difference between its morning and evening values. In this sense, statistically significant changes between morning and evening values were found only in 4 parameters: a significant increase in patients’ afternoon values of serum creatinine (they reached AKI criteria), sodium, and urinary osmolarity levels, as well as a significant reduction in their uric acid levels, compared to their morning values.

Discussion

Other studies performed in rural workers under similar working and weather conditions have reported similar findings. Kupferman et al. carried out a study based on 326 workers in Nicaragua during the harvest season, and they found that 10.4% (n = 34) of the workers developed AKI during harvest, of which 85% were sugarcane cutters. In addition, multiple linear regression models for serum creatinine showed that working as a cane cutter during harvest was associated with a 16% increase in serum creatinine value (8). Peraza et al. conducted a study (n = 664 participants) in El Salvador, between the third and seventh decade of life, in various sort of agricultural jobs and at different altitudes above sea level: 0-50 m, 500-650 m, and 1,650 m, demonstrating that in the communities who were located lower in respect to sea level, 19% of workers showed a decrease in GFR <60 ml / min per 1.73 m². However, this condition was not observed in workers who were more than 500 m above sea level (9). Although MeN is currently recognized as an independent entity, for many authors it seems to be a variety of a chronic nephropathy reported in different parts of the world, with a common denominator which consists of its apparition in agricultural workers exposed to extreme muscular effort, poor hydration status and very hot climates in low areas (8-12).

In this sense, there is controversy regarding which of the aforementioned inducing factors (extremely hot weather, dehydration status, etc.) could mainly contribute to the appearance of this entity. Regarding excessive physical exertion, recent studies have put in doubt its benefits since they documented a “J curve” in its association with general mortality. Respecting the possible relationship between a hard physical activity with the appearance of acute kidney injury, various mechanisms have been postulated (13-15): First, extreme exercise promotes renal hypoperfusion, and consequently leads to glomerular filtration rate reduction. This phenomenon can be exacerbated by volume depletion due to excessive fluid loss and its inadequate replacement, as well as an extreme intra-renal vasoconstriction as a result of a marked sympathetic system activation (increased catecholamines), and renal vasoconstrictor hormones release, as is the case of vasopressin, and renin-angiotensin-aldosterone system. It should be noted that intrarenal vasospasm as a mechanism of AKI has already been documented in the ALPE syndrome: exercise-induced AKI developing after anaerobic exercises (13-15). Second, renal damage induced by substances which are high in serum compartment, mainly as a consequence of rhabdomyolysis, such as phosphorus, uric acid (crystal nephropathy) and myoglobin (pigment nephropathy) can induce renal damage. These substances can precipitate within the proximal tubules, causing obstruction and exacerbating their toxic impact. The tendency for intra-tubular precipitation is intensified by the elevated concentration and acidity of urine in this environment (13,14). There are different mechanisms through which uric acid can cause kidney injury, such as: renal autoregulation alteration, intra-renal vasoconstriction, endothelial dysfunction, as well as uric acid pro-inflammatory (increased IL-6) and pro-oxidative effects (15-20). Third, regarding the hypothesis that recurrent heat stress (heat stroke) could lead to renal damage, it has been postulated that it could act by promoting critical fluid contraction, muscle thermal damage, as well as vasoconstrictor substances release (13,21). In addition, it has been proposed that repetitive dehydration leads to tubular damage and parenchymal fibrosis since during dehydration aldose reductase and fructokinase enzymes are activated in renal tubules, inducing higher intratubular fructose synthesis, higher fructose metabolism, and consequently increased oxidative tubule-interstitial damage (18). Moreover, this clinical scenario usually is worsened by the workers’ cultural customs of drinking fructose-containing drinks (9,13). However, some authors do not consider this mechanism as the main inducing factor of CINAC. They base their statement in a series of facts which are summarized in the PRO column of Table 2 (5).

Table 2: Arguments in favor (PRO) or against (CON) dehydration as the main inducing factor of chronic interstitial nephritis in agricultural communities (CINAC)

Source: Own elaboration.

Fourth, other authors attribute a prominent role to nephrotoxicity induced by NSAIDs, heavy metals, and/or agrochemicals (fertilizers and pesticides) (9-13). Pesticides contain nephrotoxic agents such as cadmium, arsenic, chromium, and other heavy metals. Chronic exposure to those substances has been associated with chronic tubulointerstitial nephritis. The damaging mechanism consists of the accumulation of these metals in proximal tubule cells, where they cause functional and structural defects. This process involves local oxidative stress, which leads to lipid peroxidation, apoptosis and necrosis of renal cells (22). Fifth, a possible genetic susceptibility to develop this condition has also been proposed, since it has been documented an association of CINAC with family history of CKD, as well as a relationship between CINAC and single nucleotide polymorphisms in the SLC13A3 and KCNA10 genes in rural workers in Sri Lanka (9). Therefore, all the above described AKI inducing mechanisms, such as extreme exercise, pigmenturia, heat stroke, nephrotoxic agents, and genetic predisposing factors could induce, individually or combined, repetitive AKI episodes in rural workers, and consequently lead them to develop CKD (23,24). In our study some volunteers presented a significant change between morning and afternoon values of the following parameters: Serum sodium, glucose, phosphorus, creatinine, urinary osmolarity levels, as well as a significant reduction in their serum potassium levels. Regarding the documented significantly higher serum sodium, serum creatinine and urinary osmolarity afternoon values compared to their morning values, they could reflect the marked status of dehydration of these workers. Besides, the documented significantly higher serum glucose afternoon values compared to their morning values, could reflect that perhaps some volunteers suffered from pre-diabetes mellitus, and/or the high stress status stand (high sympathetic tone) by these workers. Concerning the documented significantly higher serum phosphorus (and serum creatinine) values compared to their morning ones, they could be explained by some degree of rhabdomyolysis induced by their harsh physical effort. Finally, the documented significantly reduced serum potassium values compared to their morning values, could be explained by and increased urinary potassium loss secondary to secondary hyperaldosteronism (induced by hypovolemia), and/or some degree of proximal tubule dysfunction (acquired or primary tubulopathy). An acute proximal tubular injury with its consequent urine uric acid loss could also explain the serum uric acid level reduction documented in the afternoon samples in our study.

In regard to the documented significantly higher serum creatinine, as well as serum sodium and urinary osmolarity afternoon values compared to their morning values, they could reflect on one hand AKI installation, and on the other hand, a status of marked dehydration, being probably their main AKI inducing mechanism. Finally, the documented significantly reduced afternoon serum uric acid values compared to their morning ones, could be explained by some degree of proximal tubule dysfunction (acquired or primary tubulopathy) and increased urinary uric acid loss or intratubular precipitation. Uric acid intratubular precipitation could be promoted by dehydration (16-20). As it was mentioned above, intratubular uric acid accumulation can induce tubular damage by promoting local ischemia, inflammation, and oxidative stress (15,20,25). Studies performed in Brazil, El Salvador and Nicaragua also found an increase in serum creatinine after a heavy workday, documenting a mean serum creatinine increase of 0.21 mg/dl, 0.12 mg/dl, and 0.12 mg/dl, respectively (22-31). Even, in the Brazilian study, 17% of the studied workers (5/28) showed a serum creatinine rise ≥ 0.3 mg/dl at the end of the workday (26). It is worth pointing out that despite the aforementioned in favor and against the role that repeated dehydration could play in the induction of CINAC, and the known worsening effect that it has in other renal conditions such as urolithiasis, and acute or chronic nephropathy of any etiology, it seems that at least severe dehydration has a co-causal role in the appearance of CINAC. Finally, since this nephropathy has also been documented in other sort of workers exposed to hot climate (masons, long haul truckers), as well as in people not-exposed to hot-stress (workers’ relatives), we prefer the term environmental-stress nephropathy to designate this entity (21). The main limitations of our study have been the relative low number of workers studied, not having been able to dose agrochemicals, nor obtain the thermal record in the field by using heat stress monitors on the day the study was carried out, as well as having studied only one agriculture setting. We plan to overcome all these limitations in our next field study.

Conclusion

Eighteen percent of the rural workers evaluated developed parameters compatible with AKI and dehydration at the end of workday in the Colombian Caribbean countryside. It is essential to clarify the role of dehydration in the development of chronic interstitial nephritis of agricultural communities (CINAC), given the simplicity of its prevention and the impact that this would have on the rural workers health.