Intranasal Administration of Sugarcane Ash Causes Chronic Kidney Disease in Rats.

Background. Silica nanoparticles found in sugarcane ash have been postulated to be a toxicant contributing to chronic kidney disease of unknown etiology (CKDu). However, while the administration of manufactured silica nanoparticles is known to cause chronic tubulointerstitial disease in rats, the effect of administering sugarcane ash on kidney pathology remains unknown. Here we investigate whether sugarcane ash can induce CKD in rats. Methods. Sugarcane ash was administered for 13 weeks into the nares of rats (5 mg/day for 5d/week), and blood, urine and kidney tissues were collected at 13 weeks (at the end of ash administration) and in a separate group of rats at 24 weeks (11 weeks after stopping ash administration). Kidney histology was evaluated, and inflammation and fibrosis (collagen deposition) measured. Results. Sugarcane ash exposure led to the accumulation of silica in the kidneys, lungs, liver and spleen of rats. Mild proteinuria developed although renal function was largely maintained. However, biopsies showed focal glomeruli with segmental glomerulosclerosis, and tubulointerstitial inflammation and fibrosis that tended to worsen even after the ash administration had been stopped. Staining for the lysosomal marker, LAMP-1, showed decreased staining in ash administered rats consistent with lysosomal activation. Conclusion. Sugarcane ash containing silica nanoparticles can cause CKD in rats.

High prevalence of chronic kidney disease of unknown etiology among workers in the Mesoamerican Nephropathy Occupational Study.

BACKGROUND: Mortality from chronic kidney disease of unknown etiology (CKDu) is extremely high along the Pacific coast of Central America, particularly among sugarcane workers. The Mesoamerican Nephropathy Occupational Study (MANOS) is a prospective cohort study of CKDu among agricultural and non-agricultural workers in El Salvador and Nicaragua. The objective of this manuscript is to describe the MANOS cohort recruitment, baseline data collection, and CKDu prevalence after two rounds. METHODS: Workers with no known diabetes, hypertension, or CKD were recruited from sugarcane, corn, plantain, brickmaking, and road construction industries (n = 569). Investigators administered questionnaires, collected biological samples, and observed workers for three consecutive workdays at the worksite. Serum specimens were analyzed for kidney function parameters, and used to calculate estimated glomerular filtration rate (eGFR). At six months, serum was collected again prior to the work shift. CKD at baseline is defined as eGFR ≤ 60 ml/min/1.73m2 at both timepoints. Age-standardized prevalence was calculated by industry, country, and demographic measures. Kidney function parameters were compared by CKD status. RESULTS: Prevalence of CKD at baseline was 7.4% (n = 42). Age-standardized prevalence was highest in Salvadoran sugarcane (14.1%), followed by Salvadoran corn (11.6%), and Nicaraguan brickmaking (8.1%). Nicaraguan sugarcane had the lowest prevalence, likely due to kidney function screenings prior to employment. CONCLUSION: Despite efforts to enroll participants without CKD, our identification of prevalent CKD among agricultural and non-agricultural workers in the MANOS cohort indicates notable kidney disease in the region, particularly among sugarcane workers.

Experimental heat stress nephropathy and liver injury are improved by allopurinol.

An epidemic of chronic kidney disease (CKD) has been observed in Central America among workers in the sugarcane fields. One hypothesis is that the CKD may be caused by recurrent heat stress and dehydration, and potentially by hyperuricemia. Accordingly, we developed a murine model of kidney injury associated with recurrent heat stress. In the current experiment, we tested whether treatment with allopurinol (a xanthine oxidase inhibitor that reduces serum urate) provides renal protection against recurrent heat stress and dehydration. Eight-week-old male C57BL/6 mice were subjected to recurrent heat stress (39.5°C for 30 min, 7 times daily, for 5 wk) with or without allopurinol treatment and were compared with control animals with or without allopurinol treatment. Mice were allowed ad libitum access to normal laboratory chow (Harlan Teklad). Kidney histology, liver histology, and renal function were examined. Heat stress conferred both kidney and liver injury. Kidneys showed loss of proximal tubules, infiltration of monocyte/macrophages, and interstitial collagen deposition, while livers of heat-stressed mice displayed an increase in macrophages, collagen deposition, and myofibroblasts. Allopurinol provided significant protection and improved renal function in the heat-stressed mice. The renal protection was associated with reduction in intrarenal uric acid concentration and heat shock protein 70 expression. Heat stress-induced renal and liver injury can be protected with allopurinol treatment. We recommend a clinical trial of allopurinol for individuals developing renal injury in rural areas of Central America where the epidemic of chronic kidney disease is occurring.

Clinical markers to predict progression from acute to chronic kidney disease in Mesoamerican nephropathy.

An epidemic of chronic kidney disease (CKD) of unknown etiology, known as Mesoamerican Nephropathy (MeN), has been ongoing in Latin America for at least two decades. MeN primarily affects young adults without traditional CKD risk factors, and agricultural workers are disproportionately afflicted. We previously identified an acute phase of MeN that involves acute kidney injury (AKI) with tubulointerstitial nephritis and systemic inflammation. Because clinical disease progression in MeN is not yet understood, we sought to determine clinical predictors for progression from acute MeN to CKD. Through ongoing surveillance in Nicaragua, local physicians reported cases of acute MeN and CKD among agricultural workers. We analyzed clinical data collected during the acute MeN encounter to identify factors associated with progression to CKD. From February 2015 to May 2017, 586 agricultural workers (median age 27.8 years, 90% male) presented with acute MeN. The majority had a normal baseline creatinine, and leukocyturia (98.8%) and peripheral leukocytosis (80.7%) were common. Ultimately, 49 (8.4%) progressed to CKD, the majority of those within 6 months. CKD was attributed to MeN in all cases, and none had diabetes or hypertension. The strongest predictors of CKD progression were anemia and paresthesias at presentation, while leukocytosis was associated with renal recovery. Clinical markers of acute MeN may help clinicians identify patients at high risk for rapid progression to CKD, which in turn can inform early clinical management. Future studies should seek to determine the underlying etiology of disease and identify optimal interventions to interrupt the pathophysiologic process of MeN.

Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy.

Mesoamerican nephropathy is a devastating disease of unknown etiology that affects mostly young agricultural workers in Central America. An understanding of the mechanism of injury and the early disease process is urgently needed and will aid in identification of the underlying cause and direct treatment and prevention efforts. We sought to describe the renal pathology in Mesoamerican nephropathy at its earliest clinical appearance in prospectively identified acute case patients in Nicaragua. We considered those with elevated (or increased at least 0.3 mg/dL or 1.5-fold from baseline) serum creatinine, leukocyturia, and either leukocytosis or neutrophilia for inclusion in this biopsy study. Renal tissue was obtained by ultrasound-guided biopsy for examination by light, immunofluorescence, and electron microscopy. All 11 individuals who underwent renal biopsy showed tubulointerstitial nephritis, with varying degrees of inflammation and chronicity. Interstitial cellular infiltrates (predominantly T lymphocytes and monocytes), mostly in the corticomedullary junction; neutrophilic accumulation in the tubular lumens; largely preserved glomeruli; few mild ischemic changes; and no immune deposits were noted. The acute components of tubulointerstitial nephritis were acute tubular cell injury, interstitial edema, and early fibrosis. Chronic tubulointerstitial nephritis included severe tubular atrophy, thickened tubular basement membrane, and interstitial fibrosis. Thus, renal histopathology in Mesoamerican nephropathy reveals primary interstitial disease with intact glomeruli.

Heat Stress Nephropathy From Exercise-Induced Uric Acid Crystalluria: A Perspective on Mesoamerican Nephropathy.

Mesoamerican nephropathy (MeN), an epidemic in Central America, is a chronic kidney disease of unknown cause. In this article, we argue that MeN may be a uric acid disorder. Individuals at risk for developing the disease are primarily male workers exposed to heat stress and physical exertion that predisposes to recurrent water and volume depletion, often accompanied by urinary concentration and acidification. Uric acid is generated during heat stress, in part consequent to nucleotide release from muscles. We hypothesize that working in the sugarcane fields may result in cyclic uricosuria in which uric acid concentrations exceed solubility, leading to the formation of dihydrate urate crystals and local injury. Consistent with this hypothesis, we present pilot data documenting the common presence of urate crystals in the urine of sugarcane workers from El Salvador. High end-of-workday urinary uric acid concentrations were common in a pilot study, particularly if urine pH was corrected to 7. Hyperuricemia may induce glomerular hypertension, whereas the increased urinary uric acid may directly injure renal tubules. Thus, MeN may result from exercise and heat stress associated with dehydration-induced hyperuricemia and uricosuria. Increased hydration with water and salt, urinary alkalinization, reduction in sugary beverage intake, and inhibitors of uric acid synthesis should be tested for disease prevention.

Mesoamerican Nephropathy or Global Warming Nephropathy?

BACKGROUND: An epidemic of chronic kidney disease (CKD) of unknown cause has emerged along the Pacific Coast of Central America. The disease primarily affects men working manually outdoors, and the major group affected is sugarcane workers. The disease presents with an asymptomatic rise in serum creatinine that progresses to end-stage renal disease over several years. Renal biopsies show chronic tubulointerstitial disease. While the cause remains unknown, recent studies suggest that it is driven by recurrent dehydration in the hot climate. Potential mechanisms include the development of hyperosmolarity with the activation of the aldose reductase-fructokinase pathway in the proximal tubule leading to local injury and inflammation, and the possibility that renal injury may be the consequence of repeated uricosuria and urate crystal formation as a consequence of both increased generation and urinary concentration, similar to a chronic tumor lysis syndrome. The epidemic is postulated to be increasing due to the effects of global warming. SUMMARY: An epidemic of CKD has led to the death of more than 20,000 lives in Central America. The cause is unknown, but appears to be due to recurrent dehydration. Potential mechanisms for injury are renal damage as a consequence of recurrent hyperosmolarity and/or injury to the tubules from repeated episodes of uricosuria. KEY MESSAGES: The epidemic of CKD in Mesoamerica may be due to chronic recurrent dehydration as a consequence of global warming and working conditions. This entity may be one of the first major diseases attributed to climate change and the greenhouse effect.

Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador--A cross-shift study of workers at risk of Mesoamerican nephropathy.

BACKGROUND: An epidemic of progressive kidney failure afflicts sugarcane workers in Central America. Repeated high-intensity work in hot environments is a possible cause. OBJECTIVES: To assess heat stress, dehydration, biomarkers of renal function and their possible associations. A secondary aim was to evaluate the prevalence of pre-shift renal damage and possible causal factors. METHODS: Sugarcane cutters (N=189, aged 18-49 years, 168 of them male) from three regions in El Salvador were examined before and after shift. Cross-shift changes in markers of dehydration and renal function were examined and associations with temperature, work time, region, and fluid intake were assessed. Pre-shift glomerular filtration rate was estimated (eGFR) from serum creatinine. RESULTS: The mean work-time was 4 (1.4-11) hours. Mean workday temperature was 34-36 °C before noon, and 39-42 °C at noon. The mean liquid intake during work was 0.8L per hour. There were statistically significant changes across shift. The mean urine specific gravity, urine osmolality and creatinine increased, and urinary pH decreased. Serum creatinine, uric acid and urea nitrogen increased, while chloride and potassium decreased. Pre-shift serum uric acid levels were remarkably high and pre-shift eGFR was reduced (<60 mL/min) in 23 male workers (14%). CONCLUSIONS: The high prevalence of reduced eGFR, and the cross-shift changes are consistent with recurrent dehydration from strenuous work in a hot and humid environment as an important causal factor. The pathophysiology may include decreased renal blood flow, high demands on tubular reabsorption, and increased levels of uric acid.

Heat stress and heat strain among outdoor workers in El Salvador and Nicaragua.

BACKGROUND: There is growing attention on occupational heat stress in Central America, as workers in this region are affected by a unique form of chronic kidney disease. Previous studies have examined wet bulb globe temperatures and estimated metabolic rates to assess heat stress, but there are limited data characterizing heat strain among these workers. OBJECTIVE: The aims were to characterize heat stress and heat strain and examine whether job task, break duration, hydration practices, and kidney function were associated with heat strain. METHODS: We used data from the MesoAmerican Nephropathy Occupational Study, a cohort of 569 outdoor workers in El Salvador and Nicaragua who underwent workplace exposure monitoring, including continuous measurement of core body temperature (Tc), heart rate (HR), physical activity, and wet bulb globe temperature (WBGT), over the course of three days in January 2018 - May 2018. Participants represented five industries: sugarcane, corn, plantain, brickmaking, and construction. RESULTS: Median WBGTs were relatively high (>27 °C) at most sites, particularly when work shifts spanned the afternoon hours (e.g., 29.2 °C among plantain workers). Sugarcane workers, especially cane cutters in both countries and Nicaraguan agrichemical applicators, had the highest estimated metabolic rates (medians: 299-318 kcal/hr). Most workers spent little time on break (<10% of the shift), as determined by physical activity data. Overall, sugarcane workers-particularly those in Nicaragua-experienced the highest Tc and HR values. However, a few workers in other industries reached high Tc (>39 °C) as well. Impaired kidney function (estimated glomerular filtration rate <90 mL/min/1.73 m2) was associated with higher Tc and HR values, even after adjustment. SIGNIFICANCE: This is the largest study to-date examining heat stress and strain among outdoor workers in Central America. Workers at sugar companies regularly experienced Tc > 38°C (76.9% of monitored person-days at Nicaraguan companies; 46.5% at Salvadoran companies). Workers with impaired kidney function had higher measures of Tc and HR. IMPACT STATEMENT: This study examined levels of occupational heat stress and heat strain experienced among outdoor workers in five industries in El Salvador and Nicaragua. We characterized heat stress using wet bulb globe temperatures and estimated metabolic rate and heat strain using core body temperature and heart rate. Sugarcane workers, particularly cane cutters and Nicaraguan agrichemical applicators, performed more strenuous work and experienced greater levels of heat strain. Impaired kidney function was associated with higher heart rates and core body temperatures.

Decreased kidney function among agricultural workers in El Salvador.

BACKGROUND: An epidemic of chronic kidney disease of unknown cause has emerged along the Pacific coast of Central America, particularly in relatively young male sugarcane workers. In El Salvador, we examined residence and occupations at different altitudes as surrogate risk factors for heat stress. STUDY DESIGN: Cross-sectional population-based survey. SETTING & PARTICIPANTS: Populations aged 20-60 years of 5 communities in El Salvador, 256 men and 408 women (participation, 73%): 2 coastal communities with current sugarcane and past cotton production and 3 communities above 500 m with sugarcane, coffee, and service-oriented economies. PREDICTOR: Participant sex, age, residence, occupation, agricultural history by crop and altitude, and traditional risk factors for CKD. OUTCOMES: Serum creatinine (SCr) level greater than the normal laboratory range for sex, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, and proteinuria categorized as low (protein excretion ≥ 30-< 300 mg/dL) and high grade (≥ 300 mg/dL). RESULTS: Of the men in the coastal communities, 30% had elevated SCr levels and 18% had eGFR < 60 mL/min/1.73 m2 compared with 4% and 1%, respectively, in the communities above 500 m. For agricultural workers, prevalences of elevated SCr levels and eGFR < 60 mL/min/1.73 m2 were highest for coastal sugarcane and cotton plantation workers, but were not increased in sugarcane workers at 500 m or subsistence farmers. Women followed a weaker but similar pattern. Proteinuria was infrequent, of low grade, and not different among communities, occupations, or sexes. The adjusted ORs of decreased kidney function for 10-year increments of coastal sugarcane or cotton plantation work were 3.1 (95% CI, 2.0-5.0) in men and 2.3 (95% CI, 1.4-3.7) in women. LIMITATIONS: The cross-sectional nature of the study limits etiologic interpretations. CONCLUSION: Agricultural work on lowland sugarcane and cotton plantations was associated with decreased kidney function in men and women, possibly related to strenuous work in hot environments with repeated volume depletion.

COVID-19 and CKD: Employment, Food Security and Healthcare in El Salvador.

Background: In Central America, the COVID-19 pandemic coexists with a devastating epidemic of chronic kidney disease of unknown origin. The consequences of these overlapping health crises remain largely unknown. Methods: We assessed vulnerability to and impact of the first wave of COVID-19 on participants in a cohort study of chronic kidney disease (CKD) in El Salvador (n = 229). Participants were contacted by phone during August and September 2020. We queried changes to employment, healthcare access, household income and food security due to the pandemic (from March 2020 until the time of the interview) and COVID-19-associated symptoms during that time. Findings: We reached 94% of the cohort (n = 215). Nearly 40% of participants reported an unexpected change in employment or work activities and 8.8% reported new unemployment due to the pandemic. Participants with CKD (n = 27) had higher odds of reporting new income insecurity, food insecurity, and reductions in medical care access due to the pandemic. COVID-19-associated symptoms (an approximation of disease) were reported in 7.0% (n = 15). Participants with CKD were more likely to report COVID-19-associated symptoms compared to those without CKD, although these differences were not statistically significant. Conclusions: Overall, participants with CKD suffered greater economic consequences as a result of the pandemic and may have experienced higher incidence of COVID-19 disease, although laboratory diagnostics would be required to draw this conclusion. Longitudinal analyses are required to comprehensively evaluate the implications of the pandemic for individuals with CKD in Central America.

Chronic kidney disease in Ecuador: An epidemiological and health system analysis of an emerging public health crisis.

The absence of a chronic kidney disease (CKD) registry in Ecuador makes it difficult to assess the burden of disease, but there is an anticipated increase in the incidence of CKD along with increasing diabetes, hypertension and population age. From 2012, augmented funding for renal replacement therapy expanded dialysis clinics and patient coverage. We conducted 73 in-depth sociological interviews with healthcare providers in eight provinces and collected quantitative epidemiological data on patients with CKD diagnoses from six national-level databases between 2015 and 2018. Datasets show a total of 17,484 dialysis patients in 2018, or 567 patients per million population (pmp), with an annual cost exceeding 11% of Ecuador's public health budget. Each year, there were 139-162 pmp new dialysis patients, while doctors reported waiting lists. The number of patients on peritoneal dialysis was static; those on hemodialysis increased over time. Only 13 of 24 provinces were found to have dialysis services, and nephrologists were clustered in major cities, which limits access, delays medical attention, and adds a travel burden on patients. Prevention and screening programs are scarce, while hospitalization is an important reality for CKD patients. CKD is an emerging public health crisis that has increased dramatically over the last decade in Ecuador and is expected to continue, making coverage for all patients impossible and the current structure, unsustainable. A patient registry would help health policymakers and administrators estimate the demand and progression of patients with consideration for comorbidities, disease stage, requirements and costs, mortality and follow-up. This should be used to help identify where to focus prevention and improved treatment efforts. Organized monitoring of CKD patients would benefit from improvements in patient referral. Community-based education and prevention programs, the strengthening of primary healthcare capacity (including basic routine tests) and improved nephrology services are also urgently needed.

Mesoamerican Nephropathy (MeN): What We Know so Far.

In 2002, a report from El Salvador described a high incidence of chronic kidney disease (CKD) of unknown cause, mostly in young males from specific coastal areas. Similar situations were observed along the Pacific Ocean coastline of other Central American countries and southern Mexico (Mesoamerica). This new form of CKD has been denominated Mesoamerican endemic nephropathy (MeN). The typical presentation of MeN is a young male from an endemic area with a family history of CKD, low eGFR, high serum creatinine, low level of albuminuria, hypokalemia, hyperuricemia, and urine urate crystals. Kidney biopsy demonstrating tubulointerstitial nephritis remains the gold standard for diagnosis but is available only for a minority. Commonly proposed causes include thermal stress/dehydration and/or exposure to environmental pollutants. However, likely, a third factor, which could be genetic or epigenetic, could contribute to the cause and development of the disease, along with social determinants. Currently, preventive measures focus on minimizing workers exposure to thermal stress/dehydration. There are many research opportunities and priorities should include clinical trials to evaluate the efficacy and safety of the current treatment protocols, along with etiological and genetic studies, and the development of kidney disease data systems. Although there is scant and controversial literature with regard s  to the etiology, diagnosis and management of the disease, our aim is to provide the reader a vision of the disease based on our experience.

Mesoamerican Nephropathy.

Mesoamerican endemic nephropathy is a type of chronic kidney disease of unknown origin, present in pockets of high prevalence along the Pacific Ocean coast of the Mesoamerican region, from southwest Mexico to Costa Rica. The disease is common in young adult men, most often yet not exclusively from agricultural communities, and with a high mortality rate. Kidney biopsy specimens show primarily tubular atrophy and interstitial fibrosis with some glomerular changes attributed to ischemia. Exposure to agrochemicals, heavy metals or metalloids, intense physical activity under heat stress with dehydration, infections, among other possible causes have been hypothesized as the culprit of the disease. Hypokalemia and hyperuricemia are frequent clinical features. Early diagnosis is key to initiate timely treatment and slow down the progression to end-stage kidney disease. At present, our knowledge about the magnitude of the disease burden imposed by Mesoamerican endemic nephropathy is clearly incomplete and its cause has not been determined. There is a need to implement epidemiologic and mechanistic research projects as well as formal chronic kidney disease and end-stage kidney disease registries in the Mesoamerican region to better understand the real extent of the epidemic, delimit risk populations, and to construct sound public health policy decisions.

Intervention to diminish dehydration and kidney damage among sugarcane workers.

Objective The aim of this study was to assess the potential to reduce kidney function damage during the implementation of a water, rest, shade (WRS) and efficiency intervention program among sugarcane workers. Methods A WRS intervention program adapted from the US Occupational Safety and Health Administration (OSHA) coupled with an efficiency program began two months into the 5-month harvest. One of the two groups of workers studied was provided with portable water reservoirs, mobile shaded tents, and scheduled rest periods. Health data (anthropometric and questionnaires), blood, and urine were collected at baseline and at three subsequent times over the course of the harvest. Daily wet bulb globe temperatures (WBGT) were recorded. Results Across a working day there were changes in biomarkers indicating dehydration (urine osmolality) and serum albumin and reduced estimated glomerular filtration rate (eGFR). Cross-shift eGFR decrease was present in both groups; -10.5 mL/min/1.73m2 [95% confidence interval (95% CI) -11.8- -9.1], but smaller for the intervention group after receiving the program. Decreased eGFR over the 5-month harvest was seen in both groups: in the one receiving the intervention -3.4 mL/min/1.73m 2(95% CI -5.5- -1.3) and in the other -5.3 (95% CI -7.9- -2.7). The decrease appeared to halt after the introduction of the intervention in the group receiving the program. Conclusion A WRS and efficiency intervention program was successfully introduced for workers in sugarcane fields and appears to reduce the impact of heat stress on acute and over-harvest biomarkers of kidney function. Further research is needed to determine whether biomarker changes predict reduced risk of chronic kidney disease in this type of work.

Clinical Evidence of Acute Mesoamerican Nephropathy.

Mesoamerican nephropathy (MeN), an epidemic of unexplained kidney disease in Central America, affects mostly young, healthy individuals. Its etiology is a mystery that requires urgent investigation. Largely described as a chronic kidney disease (CKD), no acute clinical scenario has been characterized. An understanding of the early disease process could elucidate an etiology and guide treatment and prevention efforts. We sought to document the earliest clinical signs in patients with suspected MeN in a high-risk population in Nicaragua. Physicians at a local hospital identified suspect cases and documented clinical/laboratory data, demographics, and medical histories. Over a 1-year period, physicians identified 255 mostly young (median 29 years), male (89.5%) patients with elevated creatinine or reduced creatinine clearance. Mean serum creatinine (2.0 ± 0.6 mg/dL) revealed a 2-fold increase from baseline, and half had stage 2 or 3 acute kidney injury. Leukocyturia (98.4%), leukocytosis (81.4%), and neutrophilia (86.2%) predominated. Nausea (59.4%), back pain (57.9%), fever (54.6%), vomiting (50.4%), headache (47.3%), and muscle weakness (45.0%) were common. A typical case of acute MeN presented with elevated (or increased ≥ 0.3 mg/dL or ≥ 1.5-fold from baseline) creatinine, no hypertension or diabetes, leukocyturia, and at least two of fever, nausea or vomiting, back pain, muscle weakness, headache, or leukocytosis and/or neutrophilia. Rapid progression (median 90 days) to CKD was recorded in 8.5% of patients. This evidence can serve as the basis of a sensitive and urgently needed case definition for disease surveillance of early-stage, acute MeN.