Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy.

Almost 30 years after the detection of chronic interstitial nephritis in agricultural communities (CINAC) its etiology remains unknown. To help define this we examined 34 renal biopsies from Sri Lanka, El Salvador, India and France of patients with chronic kidney disease 2-3 and diagnosed with CINAC by light and electron microscopy. In addition to known histopathology, we identified a unique constellation of proximal tubular cell findings including large dysmorphic lysosomes with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound "aggregates". These aggregates associated with varying degrees of cellular/tubular atrophy, apparent cell fragment shedding and no-weak proximal tubular cell proliferative capacity. Identical lysosomal lesions, identifiable by electron microscopy, were observed in 9% of renal transplant implantation biopsies, but were more prevalent in six month (50%) and 12 month (67%) protocol biopsies and in indication biopsies (76%) of calcineurin inhibitor treated transplant patients. The phenotype was also found associated with nephrotoxic drugs (lomustine, clomiphene, lithium, cocaine) and in some patients with light chain tubulopathy, all conditions that can be directly or indirectly linked to calcineurin pathway inhibition or modulation. One hundred biopsies of normal kidneys, drug/toxin induced nephropathies, and overt proteinuric patients of different etiologies to some extent could demonstrate the light microscopic proximal tubular cell changes, but rarely the electron microscopic lysosomal features. Rats treated with the calcineurin inhibitor cyclosporine for four weeks developed similar proximal tubular cell lysosomal alterations, which were absent in a dehydration group. Overall, the finding of an identical proximal tubular cell (lysosomal) lesion in CINAC and calcineurin inhibitor nephrotoxicity in different geographic regions suggests a common paradigm where CINAC patients undergo a tubulotoxic mechanism similar to calcineurin inhibitor nephrotoxicity.

Acetylcholinesterase inhibitor insecticides related acute poisoning, availability and sales: trends during the post-insecticide-ban period of Anuradhapura, Sri Lanka.

BACKGROUND: Acetylcholinesterase inhibitor insecticides (AChEIIs) were used extensively in the agrarian region of Anuradhapura for the past few decades. As a result, the region faced a heightened risk of toxicity. Carbaryl, carbofuran, chlorpyrifos, dimethoate, and fenthion were the five hazardous AChEIIs banned from Anuradhapura in 2014. Assessment of post-ban trends in acute poisoning will reveal the impact of the ban. Data on availability and sales of remaining AChEIIs will guide towards preventive measures against related toxicities. METHODS: Cross-sectional surveys were conducted at Anuradhapura district of Sri Lanka. Details related to acute AChEII poisoning were sorted from the Teaching Hospital Anuradhapura. Main insecticide vendors in Anuradhapura were surveyed to find information on availability and sales of AChEIIs. Chi-square for goodness of fit was performed for trends in acute poisoning and sales. RESULTS: Hospital admissions related to acute AChEII poisoning have declined from 554 in 2013 to 272 in 2017. Deaths related to acute AChEII poisoning have declined from 27 in 2013 to 13 in 2017. Sales of all five banned AChEIIs had reduced by 100%. Sales of the remaining AChEIIs were declining, except for acephate, phenthoate, and profenofos. However, one of the top selling, most frequently abused carbosulfan, had the highest risk of toxicity. Chi-square for goodness of fit showed a significance (P < 0.001) between the trends of hospital admissions for acute AChEII poisoning and the sales related to AChEIIs. CONCLUSIONS: Hospital admissions related to acute poisoning was declining along with the overall sales of remaining AChEIIs, during the post-AChEII ban period. Nevertheless, future vigilance is needed on the remaining AChEIIs to predict and prevent related toxicities.

Red blood cell acetylcholinesterase activity among healthy dwellers of an agrarian region in Sri Lanka: a descriptive cross-sectional study.

BACKGROUND: Assessment of acetylcholinesterase-inhibitor insecticide (AChEII) toxicity depends on the measurement of red blood cell acetylcholinesterase (RBC-AChE) activity. Its interpretation requires baseline values which is lacking in scientific literature. We aim to find the measures of central tendency and variation for RBC-AChE activity among dwellers of Anuradhapura, where the use and abuse of AChEIIs were rampant for the last few decades. METHODS: A descriptive cross-sectional study with a community-based sampling for 100 healthy non-farmers (male:female = 1:1) was done using pre-determined selection criteria. Duplicate measurements of RBC-AChE activity were performed according to the modified Ellman procedure. Pearson's correlation and regression analysis were sort for RBC-AChE activity against its possible determinants. RESULTS: RBC-AChE activity had a mean of 449.8 (SD 74.2) mU/µM Hb with a statistical power of 0.847. It was similar to values of "healthy controls" from previous Sri Lankan toxicological studies but was low against international reference value [586.1 (SD 65.1) mU/µM Hb]. None of the possible determinants showed a significant strength of relationship with RBC-AChE activity. CONCLUSION: The baseline RBC-AChE activity among people of Anuradhapura is low in comparison with international reference values. This arises a need to find a causative mechanism.

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.

Availability of essential medicines in selected public, primary and secondary health care institutions of a rural Sri Lankan district: a spot survey.

BACKGROUND: Assessment of the availability of essential medicines, in rural areas of countries with free state health care system, is scarce. Dependence on essential medicines among the population in rural sector is considered to be high. Assessing the availability of essential medicines in selected state owned primary and secondary health care institutions of a rural district will help to identify areas where improvement is needed. METHODS: A descriptive cross sectional study, covering selected five primary and one secondary care institutions of a rural Sri Lankan district, was conducted. The national list of essential medicines, Sri Lanka was used as the check list and the guidelines of the WHO-Health Action International were adapted. RESULTS: The secondary care institution recorded an overall availability of 71%, whereas the average overall availability of the primary care institutions was 56%. Central dispensaries recorded the lowest availability. Lack of availability of medicines needed for the management of chronic kidney disease, snake bite and poisoning was noted. CONCLUSIONS: Availability of essential medicines in most of the primary and the secondary care institutions were fairly high. Deficiency in medicines needed for the management of emergencies was noted. A need based annual estimate of medicines based on an essential medicine list is suggested.

Reverse osmosis plant maintenance and efficacy in chronic kidney disease endemic region in Sri Lanka.

OBJECTIVE: Chronic Interstitial Nephritis in Agricultural Communities (CINAC) causes major morbidity and mortality for farmers in North-Central province (NCP) of Sri Lanka. To prevent the CINAC, reverse osmosis (RO) plants are established to purify the water and reduce the exposure to possible nephrotoxins through drinking water. We assessed RO plant maintenance and efficacy in NCP. METHODS: We have interviewed 10 RO plant operators on plant establishment, maintenance, usage and funding. We also measured total dissolved solids (TDS in ppm) to assess the efficacy of the RO process. RESULTS: Most RO plants were operated by community-based organizations. They provide clean and sustainable water source for many in the NCP for a nominal fee, which tends to be variable. The RO plant operators carry out RO plant maintenance. However, maintenance procedures and quality management practices tend to vary from an operator to another. RO process itself has the ability to lower the TDS of the water. On average, RO process reduces the TDS to 29 ppm. CONCLUSIONS: The RO process reduces the impurities in water available to many individuals within CINAC endemic regions. However, there variation in maintenance, quality management, and day-to-day care between operators can be a cause for concern. This variability can affect the quality of water produced by RO plant, its maintenance cost and lifespan. Thus, uniform regulation and training is needed to reduce cost of maintenance and increase the efficacy of RO plants.

Drinking well water and occupational exposure to Herbicides is associated with chronic kidney disease, in Padavi-Sripura, Sri Lanka.

BACKGROUND: The chronic kidney disease of unknown etiology (CKDu) among paddy farmers in was first reported in 1994 and has now become most important public health issue in dry zone of Sri Lanka. The objective was to identify risk factors associated with the epidemic in an area with high prevalence. METHODS: A case control study was carried out in Padavi-Sripura hospital in Trincomalee district. CKDu patients were defined using health ministry criteria. All confirmed cases (N = 125) fulfilling the entry criteria were recruited to the study. Control selection (N = 180) was done from people visiting the hospital for CKDu screening. Socio-demographic and data related to usage of applying pesticides and fertilizers were studied. Drinking water was also analyzed using ICP-MS and ELISA to determine the levels of metals and glyphosate. RESULTS: Majority of patients were farmers (N = 107, 85.6%) and were educated up to 'Ordinary Level' (N = 92, 73.6%). We specifically analyzed for the effect modification of, farming by sex, which showed a significantly higher risk for male farmers with OR 4.69 (95% CI 1.06-20.69) in comparison to their female counterparts. In the multivariable analysis the highest risk for CKDu was observed among participants who drank well water (OR 2.52, 95% CI 1.12-5.70) and had history of drinking water from an abandoned well (OR 5.43, 95% CI 2.88-10.26) and spray glyphosate (OR 5.12, 95% CI 2.33-11.26) as a pesticide. Water analysis showed significantly higher amount of hardness, electrical conductivity and glyphosate levels in abandoned wells. In addition Ca, Mg, Ba, Sr, Fe, Ti, V and Sr were high in abandoned wells. Surface water from reservoirs in the endemic area also showed contamination with glyphosate but at a much lower level. Glyphosate was not seen in water samples in the Colombo district. CONCLUSION: The current study strongly favors the hypothesis that CKDu epidemic among farmers in dry zone of Sri Lanka is associated with, history of drinking water from a well that was abandoned. In addition, it is associated with spraying glyphosate and other pesticides in paddy fields. Farmers do not use personnel protective equipments and wears scanty clothing due to heat when spraying pesticides.

Simultaneous exposure to multiple heavy metals and glyphosate may contribute to Sri Lankan agricultural nephropathy.

BACKGROUND: Sri Lankan Agricultural Nephropathy (SAN), a new form of chronic kidney disease among paddy farmers was first reported in 1994. It has now become the most debilitating public health issue in the dry zone of Sri Lanka. Previous studies showed SAN is a tubulo-interstitial type nephropathy and exposure to arsenic and cadmium may play a role in pathogenesis of the disease. METHODS: Urine samples of patients with SAN (N = 10) from Padavi-Sripura, a disease endemic area, and from two sets of controls, one from healthy participants (N = 10) from the same endemic area and the other from a non-endemic area (N = 10; Colombo district) were analyzed for 19 heavy metals and for the presence of the pesticide- glyphosate. RESULTS: In both cases and the controls who live in the endemic region, median concentrations of urinary Sb, As, Cd, Co, Pb, Mn, Ni, Ti and V exceed the reference range. With the exception of Mo in patients and Al, Cu, Mo, Se, Ti and Zn in endemic controls, creatinine adjusted values of urinary heavy metals and glyphosate were significantly higher when compared to non-endemic controls. Creatinine unadjusted values were significant higher for 14 of the 20 chemicals studied in endemic controls and 7 in patients, compared to non-endemic controls. The highest urinary glyphosate concentration was recorded in SAN patients (range 61.0-195.1 µg/g creatinine). CONCLUSIONS: People in disease endemic area exposed to multiple heavy metals and glyphosate. Results are supportive of toxicological origin of SAN that is confined to specific geographical areas. Although we could not localize a single nephrotoxin as the culprit for SAN, multiple heavy metals and glyphosates may play a role in the pathogenesis. Heavy metals excessively present in the urine samples of patients with SAN are capable of causing damage to kidneys. Synergistic effects of multiple heavy metals and agrochemicals may be nephrotoxic.

Importance of Arsenic and pesticides in epidemic chronic kidney disease in Sri Lanka.

In a recent study published by the National Project team on chronic kidney diseases of unknown origin in Sri Lanka, we believe there to be flaws in the design, analysis, and conclusions, which should be discussed further. The authors wanted to emphasis Cadmium as the major risk factor for chronic kidney disease of unknown etiology in Sri Lanka while undermining the importance of Arsenic and nephrotoxic pesticides. To arrive at predetermined conclusions the authors appear have changed and misinterpreted their own results. The enormous pressure applied by the agrochemical industry on this issue may be a factor. Herein, we discuss these issues in greater detail.

Chronic interstitial nephritis in agricultural communities: a new perspective on etiology, diagnosis and mechanism.

Chronic interstitial nephritis in agricultural communities is a devastating kidney disease with a globally increasing prevalence. Its cause is unknown. Two predominant etiologies are hypothesised: recurrent episodes of dehydration and exposure to environmental toxins, such as agrochemicals and metals. In this review, we summarise arguments on: 1) why heat stress/dehydration is an unlikely cause of this disease and 2) why chronic interstitial nephritis in agricultural communities is to be considered a toxin-induced nephropathy. Mechanistically, we provide arguments for a putative role of pesticides on the one hand, and the calcineurin pathway on the other hand, both of which require further investigation. Finally, we summarise several important perspectives for research on chronic interstitial nephritis in agricultural communities.

The Utility of Novel Renal Biomarkers in Assessment of Chronic Kidney Disease of Unknown Etiology (CKDu): A Review.

Chronic Kidney Disease (CKD) is a globally prevalent non-communicable disease with significant mortality and morbidity. It is typically associated with diabetes and hypertension; however, over the last two decades, an emergence of CKD of unknown etiology (CKDu) has claimed thousands of lives in several tropical agricultural communities. CKDu is associated with gradual loss of renal function without initial symptoms until reaching complete kidney failure and eventually death. The most impacted are young adult males of lower socio-economic strata. Since the disease progression can be successfully attenuated through early detection, the development of superior screening and management measures is of utmost importance. In contrast to the conventional biomarkers, novel biomarkers with improved sensitivity and specificity are being discussed as promising tools for early diagnosis of the disease. This review summarizes emerging novel biomarkers used in assessing CKD and discusses the current utility and diagnostic potential of such biomarkers for CKDu screening in clinical settings of different communities impacted by CKDu. Our goal is to provide a framework for practitioners in CKDu impacted regions to consider the use of these novel biomarkers through this synthesis. The increased use of these biomarkers will not only help to validate their diagnostic power further and establish potential prognostic value but may also provide critical insights into sites and mechanisms of renal damage.

Chronic Interstitial Nephritis in Agricultural Communities (CINAC) in Sri Lanka.

A significant increase in cases of chronic kidney disease has been observed in the dry zone of Sri Lanka. This unusual chronic kidney disease was first reported in the early 1990s among middle-aged paddy farmers. Considering epidemiologic and histopathologic findings, the disease recently was named chronic interstitial nephritis in agricultural communities (CINAC). Twenty-five years after the first report, CINAC is the most significant public health issue in the paddy farming areas with more than 70,000 estimated patients and many deaths. Histopathologically, this disease is a tubular interstitial nephritis associated with glomerular sclerosis and mild vascular changes. Morphologic and biochemical characteristics of CINAC in Sri Lanka share many similarities with Mesoamerican nephropathy. Certain natural and man-made toxins, heat stress with repeated volume and salt depletion, infections such as hantavirus and leptospirosis, and a genetic origin have been proposed and investigated as possible etiologies, and an association between CINAC and herbicides is widely discussed. Several preventive measures already have been implemented by health authorities in Sri Lanka to minimize nephrotoxin exposure and well hydrate the inhabitants in the disease-endemic region. The impact of these interventions will be watched with anticipation.

In vivo, ex vivo and in vitro evidence for atropine-mediated attenuation of glucagon-like peptide-1 secretion: findings from a systematic review.

Glucagon-like peptide-1 (GLP-1) is involved in postprandial glucose homeostasis. Secretion of which involves a cholinergic pathway. Anticholinergic agent like atropine could act as a competitive antagonist of acetylcholine at muscarinic receptors. This review explores studies that assess the role of atropine in GLP-1 secretion. We selected published original articles from PubMed, Science Direct, The Cochrane Library, Trip, Google and the reference lists of the selected articles. Reporting was done according to the PRISMA statement. Relevant standard and previously published tools were used to assess the risk of bias of the selected articles. Twelve articles out of 185 search results fulfilled the review criteria. Eight were in vivo studies (six animal and two human studies), three were ex vivo studies and one was an in vitro study. Animal studies had rats, mice, pigs and monkeys as the subjects. Human studies involved healthy men and women. Majority of the studies reported an atropine-mediated attenuation of GLP-1 secretion and postprandial secretion of GLP-1 was mainly affected. However, atropine failed to significantly affect GLP-1 secretion when dipeptidyl peptidase-4 (DPP-4) enzyme was inhibited.

Comparison of biochemical parameters among DPP4 inhibitor users and other oral hypoglycaemic drug users: a cross-sectional study from Anuradhapura, Sri Lanka.

BACKGROUND: Higher efficacy of incretin-based therapies for type 2 diabetes mellitus has been reported from Asia. Pancreatitis and hepatitis have also been suspected to occur due to dipeptidyl peptidase-4 inhibitor (DPP4I) treatment. The present study aims at comparing selected biochemical parameters among DPP4 inhibitor users and other oral hypoglycaemic drug users. METHODS: Patients were recruited from the State Pharmaceutical Corporation, Anuradhapura, Sri Lanka, for a comparative cross-sectional study. Two groups were involved: "DPP4I" user group (n = 63) and "other oral hypoglycaemic" user group (n = 126). Mann-Whitney U test was performed to find a significant difference (p < 0.05) in the distributions of HbA1C, pancreatic amylase, serum lipase, AST and ALT levels between the two groups. RESULTS: Contradicting to previous Asian studies, distribution of HbA1C (p = 0.569) between anti-diabetic regimes with and without DPP4 inhibitors showed no significant difference. Also, amylase (p = 0.171), AST (p = 0.238) and ALT (p = 0.347) failed to show significance. However, lipase was significantly (p = 0.012) high in the DPP4I group. CONCLUSION: The study showed a significantly higher lipase level among the DPP4I users in comparison to other oral hypoglycaemic drug users, and possible reasons were discussed.

A low GLP-1 response among patients treated for acute organophosphate and carbamate poisoning: a comparative cross-sectional study from an agrarian region of Sri Lanka.

Higher incidence of diabetes along with increased use of pesticides is seen in Southeast Asia. Recent hypothesis postulated a link between acetylcholinesterase inhibitor insecticides and type 2 diabetes through the GLP-1 pathway. This study compares the GLP-1 response between groups with low and high red blood cell acetylcholinesterase (RBC-AChE) activity. A comparative cross-sectional study was conducted amongst patients who were within 3 months after an acute organophosphate or carbamate poisoning (acute group) and amongst vegetable farmers with low (chronic group) and high (control group) RBC-AChE activity. Acute (366 mU/µM Hb) and chronic (361 mU/µM Hb) groups had significantly lower RBC-AChE activity in comparison to the control (471 mU/µM Hb) group (P < 0.0001). Only the acute group, which has had atropine therapy, showed a significantly lower 120 min value in comparison to the control group (P = 0.0028). Also, the acute group had significantly low late (P = 0.0287) and total (P = 0.0358) responses of GLP-1 in comparison to the control group. The findings of the study allude towards attenuation of GLP-1 response amongst patients after acute organophosphate and carbamate poisoning. The possibility of an atropine-mediated attenuation of GLP-1 response was discussed.

Comparison of medication adherence between type 2 diabetes mellitus patients who pay for their medications and those who receive it free: a rural Asian experience.

BACKGROUND: Treatment plans fail if patients have poor medication adherence. Our aim was to compare medication adherence, reasons for non-adherence, and satisfaction with community support among type 2 diabetes mellitus patients who pay for their medications and those who receive it free. METHODS: A descriptive cross-sectional study was conducted at Anuradhapura, Sri Lanka, among patients who were on oral anti-diabetic drugs for at least 3 months. They were grouped into two: universal-free group and fee-paying group. Three different scales were used to score medication adherence, reasons for non-adherence, and satisfaction with community support. Fisher's exact test was performed to determine if there was a significant difference between the two groups (p < 0.05) concerning medication adherence and satisfaction with community support. RESULTS: The median (IQR) medication adherence scores for fee-paying group and universal-free group were 3 (2-3) and 3 (3-3), respectively; the median (IQR) scores for satisfaction with community support were 5 (2-6) and 4 (4-6), respectively. Both the adherence and the satisfaction failed to show a significant difference between the two groups. Forgetfulness, being away from home, complex drug regime, and willingness to avoid side effects were common reasons of non-adherence for both the groups. CONCLUSIONS: There was no significant difference in medication adherence between the universal-free group and fee-paying group, despite of having a significantly different income. The universal-free health service would be a probable reason.

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.

A novel ultrasound technique to detect early chronic kidney disease.

Chronic kidney disease (CKD) of unknown etiology is recognized as a major public health challenge and a leading cause of morbidity and mortality in the dry zone in Sri Lanka. CKD is asymptomatic and are diagnosed only in late stages. Evidence points to strong correlation between progression of CKD and kidney fibrosis. Several biochemical markers of renal fibrosis have been associated with progression of CKD. However, no marker is able to predict CKD consistently and accurately before being detected with traditional clinical tests (serum creatinine, and cystatin C, urine albumin or protein, and ultrasound scanning). In this paper, we hypothesize that fibrosis in the kidney, and therefore the severity of the disease, is reflected in the frequency spectrum of the scattered ultrasound from the kidney. We present a design of a simple ultrasound system, and a set of clinical and laboratory studies to identify spectral characteristics of the scattered ultrasound wave from the kidney that correlates with CKD. We believe that spectral parameters identified in these studies can be used to detect and stratify CKD at an earlier stage than what is possible with current markers of CKD.