Melatonin ameliorates renal dysfunction in glyphosate- and hard water-treated mice.

Chronic interstitial nephritis in agricultural communities (CINAC) is a severe and widespread disease that has been associated with environmental and occupational exposure to glyphosate and hard water. However, the potential underlying mechanisms remain incompletely understood. Melatonin is reported to exert protective effects on the kidney, but whether melatonin can attenuate renal tubular injury in mice exposed to glyphosate combined with hard water is unclear. Here, mice were treated with high doses and environmentally relevant doses of glyphosate (100 mg/kg·bw and 0.7 mg/L, respectively) and/or hard water (2500 mg/L CaCO3 and 250 mg/L Ca2+, respectively) via their drinking water for 12 weeks. We found that high-dose glyphosate or hard water treatment significantly increased the levels of biomarkers of renal damage, including ß2-microglobulin, neutrophil gelatinase-associated lipid carrier protein, and/or albumin, in the urine; these increased biomarker levels were correlated with obvious morphological changes, and all of these changes were also observed in animals exposed to environmentally relevant doses of glyphosate and/or high Ca2+ water. Melatonin (10 mg/kg·bw, intraperitoneal injection, daily for 12 weeks) administered concomitantly with high doses of glyphosate and hard water inhibited the glyphosate- and hard water-induced increases in the levels of kidney injury biomarkers and changes in morphology; this result was intriguing. Additionally, glyphosate combined with hard water at both high and environmentally relevant doses significantly upregulated the expression of the endoplasmic reticulum (ER) stress marker proteins Bip, ATF6, and PERK as well as the pyroptosis-related proteins (NLRP3 and caspase 1 signaling proteins) in renal tissues. Similarly, melatonin significantly attenuated the increased ER stress and pyroptosis induced by high doses of glyphosate and hard water. In summary, we conclude that exposure to glyphosate and hard water at both high doses and environmentally relevant doses causes renal dysfunction in mice, and this dysfunction can be attenuated by melatonin, possibly through the inhibition of ER stress and pyroptosis. Our results support the notion that melatonin may have therapeutic potential for the treatment of chronic kidney diseases.

Prevalence and risk factors for impaired kidney function in the district of Anuradhapura, Sri Lanka: a cross-sectional population-representative survey in those at risk of chronic kidney disease of unknown aetiology.

BACKGROUND: Over the last 20 years there have been reports of a form of chronic kidney disease of unknown cause (CKDu) affecting rural communities in the North Central Province of Sri Lanka. Valid prevalence estimates, using a standardised methodology, are needed to assess the burden of disease, assess secular trends, and perform international comparisons. METHODS: We conducted a cross-sectional representative population survey in five study areas with different expected prevalences of CKDu. We used a proxy definition of CKDu involving a single measure of impaired kidney function (eGFR< 60 mL/min/1.7m2, using the CKD-Epi formula) in the absence of hypertension, diabetes or heavy proteinuria. RESULTS: A total of 4803 participants (88.7%) took part in the study and 202 (6.0%; 95% CI 5.2-6.8) had a low eGFR in the absence of hypertension, diabetes and heavy proteinuria and hence met the criteria for proxy CKDu. The proportion of males (11.2%; 95% CI 9.2-13.1) were triple than the females (3.7%; 95% CI 2.9-4.5). Advancing age and history of CKD among parents or siblings were risk factors for low GFR among both males and females while smoking was found to be a risk factor among males. CONCLUSIONS: These data, collected using a standardised methodology demonstrate a high prevalence of impaired kidney function, not due to known causes of kidney disease, in the selected study areas of the Anuradhapura district of Sri Lanka. The aetiology of CKDu in Sri Lanka remains unclear and there is a need for longitudinal studies to describe the natural history and to better characterise risk factors for the decline in kidney function.

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.

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.

Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants.

Increase in the prevalence of chronic kidney disease (CKD) is observed in Central America, Sri Lanka and other tropical countries. It is named chronic interstitial nephritis in agricultural communities (CINAC). CINAC is defined as a form of CKD that affects mainly young men, occasionally women. Its aetiology is not linked to diabetes, hypertension, glomerulopathies or other known causes. CINAC patients live and work in poor agricultural communities located in CINAC endemic areas with a hot tropical climate, and are exposed to toxic agrochemicals through work, by ingestion of contaminated food and water, or by inhalation. The disease is characterized by low or absent proteinuria, small kidneys with irregular contours in CKD stages 3­4 presenting tubulo-interstitial lesions and glomerulosclerosis at renal biopsy. Although the aetiology of CINAC is unclear, it appears to be multifactorial. Two hypotheses emphasizing different primary triggers have been proposed: one related to toxic exposures in the agricultural communities, the other related to heat stress with repeated episodes of dehydration heath stress and dehydration. Existing evidence supports occupational and environmental toxins as the primary trigger. The heat stress and dehydration hypothesis, however, cannot explain: why the incidence of CINAC went up along with increasing mechanization of paddy farming in the 1990s; the non-existence of CINAC in hotter northern Sri Lanka, Cuba and Myanmar where agrochemicals are sparsely used; the mosaic geographical pattern in CINAC endemic areas; the presence of CINAC among women, children and adolescents who are not exposed to the harsh working conditions; and the observed extra renal manifestations of CINAC. This indicates that heat stress and dehydration may be a contributory or even a necessary risk factor, but which is not able to cause CINAC by itself.

Mesoamerican Endemic Nephropathy (MeN): A Disease Reported in Adults That May Start Since Childhood?

Mesoamerican endemic nephropathy (MeN) is a type of chronic kidney disease (CKD) of uncertain etiology that occurs along the Pacific coast of the southern part of Mexico and Central America. During the past 20 years MeN has become a leading cause of death in the region, clamming close to 50,000 lives, with 40% of these deaths occurring in young people. The cause remains unknown, but most researchers believe in a multifactorial etiology that includes social determinants of poverty. Existing evidence suggests that subclinical kidney injury begins early in life and leads to a higher than expected prevalence of CKD among children in Central America. Access to health services in the region, specifically kidney replacement therapy, remains limited. We proposed a strategy to address the perceived needs and urge coordinated efforts of governments, academic organizations, and international bodies to develop a comprehensive plan of action to mitigate this situation among the vulnerable and economically disadvantaged population.

Involvement of mitochondrial fission in renal tubular pyroptosis in mice exposed to high and environmental levels of glyphosate combined with hard water.

Chronic interstitial nephritis in agricultural communities (CINAC) has reached epidemic proportions. The combination of glyphosate and hard water has been postulated to play a potent aetiological role in CINAC. Therefore, dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission and subsequent activation of the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (Nlrp3)/caspase1 pathway may be involved in the pathogenesis of nephropathy. In the present study, mice were sub-chronically exposed to high doses and environmental levels of glyphosate (100 mg/kg body weight (mg/kg·bw) glyphosate in Roundup and 0.7 mg/L pure glyphosate, respectively) and hard water (2500 mg/L CaCO3 and 250 mg/L Ca2+, respectively) in drinking water. Moreover, Mdivi-1 (Md-1, 10 mg/kg·bw) was intraperitoneally injected to inhibit Drp1 on the basis of the high-dose experiment. Histopathological examination, biochemical analysis, ELISA, western blotting and fluorescent staining were used to analyse renal structure, renal tubular pyroptosis and mitochondrial fission/fusion alterations. The results showed dramatic proximal tubular injury, particularly in the combined groups. Moreover, significant increases in the protein expression levels of calmodulin (CaM), calmodulin-dependent protein kinase II (CaMKII), Drp1/p-Drp1-Ser616 and the Txnip/Nlrp3/caspase1 signalling pathway, and alterations in oxidative stress were observed in the combined groups, and these effects were attenuated by the Drp1 inhibitor Md-1. Intriguingly, there may be a synergistic effect of glyphosate and hard water on renal injury. Taken together, these results suggest that the combination of glyphosate and hard water, even at environmental exposure levels, enhances pyroptosis and ongoing tubulointerstitial inflammation through excessive Drp1-mediated mitochondrial fission.

Kidney Diseases in Agricultural Communities: A Case Against Heat-Stress Nephropathy.

The beginning of the 21st century has seen the emergence of a new chronic tubulo-interstitial kidney disease of uncertain cause among agricultural communities in Central America and Sri Lanka. Despite many similarities in demography, presentation, clinical features, and renal histopathology in affected individuals in these regions, a toxic etiology has been considered mainly in Sri Lanka, whereas the predominant hypothesis in Central America has been that recurrent acute kidney injury (AKI) caused by heat stress leads to chronic kidney disease (CKD). This is termed the heat stress/dehydration hypothesis. This review attempts to demonstrate that there is sparse evidence for the occurrence of significant AKI among manual workers who are at high risk, and that there is little substantial evidence that an elevation of serum creatinine < 0.3 mg/dl in previously healthy people will lead to CKD even with recurrent episodes. It is also proposed that the extent of global warming over the last half-century was not sufficient to have caused a drastic change in the effects of heat stress on renal function in manual workers. Comparable chronic tubulo-interstitial kidney disease is not seen in workers exposed to heat in most tropical regions, although the disease is seen in individuals not exposed to heat stress in the affected regions. The proposed pathogenic mechanisms of heat stress causing CKD have not yet been proved in humans or demonstrated in workers at risk. It is believed that claims of a global warming nephropathy in relation to this disease may be premature and without convincing evidence.

Toward a Comprehensive Hypothesis of Chronic Interstitial Nephritis in Agricultural Communities.

Over the past 20 years, there has been an increase in chronic interstitial nephritis in agricultural communities (CINAC) not associated with traditional risk factors. This disease has become an important public health problem and is observed in several countries in Central America and Asia. CINAC predominantly affects young male farmers between the third and fifth decades of life with women, children, and adolescents less often affected. Clinically, CINAC behaves like a chronic tubulointerstitial nephropathy but with systemic manifestations not attributable to kidney disease. Kidney biopsy reveals chronic tubulointerstitial nephritis with variable glomerulosclerosis and mild chronic vascular damage, with the severity depending on sex, occupation, and CKD stage. The presence of toxicological, occupational, and environmental risk factors within these communities suggests a multifactorial etiology for CINAC. This may include exposure to agrochemicals, a contaminated environment, repeated episodes of dehydration with heat stress, and an underlying genetic predisposition. An understanding of these interacting factors using a multidisciplinary approach with international cooperation and the formulation of a comprehensive hypothesis are essential for the development of public health programs to prevent this devastating epidemic.