Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities.

CINAC-patients present renal proximal tubular cell lysosomal lesions which are also observed in patients experiencing calcineurin inhibitor (CNI) nephrotoxicity, suggesting that CINAC is a toxin-induced nephropathy. An alternative hypothesis advocates chronic dehydration as a major etiological factor for CINAC. Here, we evaluated histological and molecular changes in dehydrated versus toxin exposed rats. Wistar rats were divided in 3 groups. Group 1 (n = 6) had free access to drinking water (control group). Group 2 (n = 8) was water deprived for 10 h per 24 h, 5 days/week and placed in an incubator (37 °C) for 30 min/h during water deprivation. Group 3 (n = 8) underwent daily oral gavage with cyclosporine (40 mg/kg body weight). After 28 days, renal function, histopathology and proteomic signatures were analysed. Cyclosporine-treated rats developed focal regions of atrophic proximal tubules with associated tubulo-interstitial fibrosis. PASM staining revealed enlarged argyrophilic granules in affected proximal tubules, identified as lysosomes by immunofluorescent staining. Electron microscopy confirmed the enlarged and dysmorphic phenotype of the lysosomes. Overall, these kidney lesions resemble those that have been previously documented in farmers with CINAC. Dehydration resulted in none of the above histopathological features. Proteomic analysis revealed that dehydration and cyclosporine both induce injury pathways, yet of a clear distinct nature with a signature of toxicity only for the cyclosporine group. In conclusion, both cyclosporine and dehydration are injurious to the kidney. However, dehydration alone does not result in kidney histopathology as observed in CINAC patients, whereas cyclosporine administration does. The histopathological analogy between CINAC and calcineurin inhibitor nephrotoxicity in rats and humans supports the involvement of an as-yet-unidentified environmental toxin in CINAC etiology.

Progression of established non-diabetic chronic kidney disease is halted by metformin treatment in rats.

Current treatment strategies for chronic kidney disease (CKD) mainly focus on controlling risk factors. Metformin, a first-line drug for type 2 diabetes, exerts beneficial pleiotropic actions beyond its prescribed use and incipient data have revealed protective effects against the development of kidney impairment. This study evaluated the therapeutic efficacy of metformin and canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor recently approved by the United States Food and Drug Administration to treat diabetic nephropathy, in slowing the progression of established non-diabetic CKD. Rats with adenine-induced CKD were assigned to different treatment groups to receive either 200 mg/kg metformin, four or five weeks after the start of the adenine diet (established mild-moderate CKD), or 25 mg/kg canagliflozin four weeks after the start of the diet, by daily oral gavage administered during four weeks. Each treatment group was compared to a vehicle group. Chronic adenine dosing resulted in severe CKD in vehicle-treated rats as indicated by a marked rise in serum creatinine levels, a marked decrease in creatinine clearance, and a disturbed mineral metabolism. Metformin, but not canagliflozin, halted functional kidney decline. Additionally, kidneys of metformin-treated animals showed less interstitial area and inflammation as compared to the vehicle group. Proteomic analyses revealed that metformin's kidney-protective effect was associated with the activation of the Hippo signaling pathway, a highly conserved multiprotein kinase cascade that controls tissue development, organ size, cell proliferation, and apoptosis. Thus, metformin demonstrated therapeutic efficacy by halting the progression of established CKD in a rat model.

Farmers' Knowledge, Attitudes, and Perceptions Regarding Carcinogenic Pesticides in Fez Meknes Region (Morocco).

Pesticides play an important role in the improvement of agricultural production, but their use may result in adverse effects on the environment, consumers, and farmers' health. As there are limited data focusing on the factors influencing safety behavior toward pesticide use in Morocco, we conducted a cross-sectional survey in 15 rural communities of Morocco's Fes Meknes region to assess the attitudes, knowledge, and practices regarding pesticide use. A structured questionnaire was completed, containing the data of the interviewed farmers, their behavior towards safety measures, the type of active ingredient used, as well as the perception of risks to their own health following exposure to pesticides by the existence of chronic, self-perceived symptoms. Non-probability (empirical) sampling with the quota method was carried out, which consists of constructing the sample. Results showed that most respondents have not been trained in the application of pesticides, with almost half of the farmers using a category of pesticides which are classified by the International Agency for Research on Cancer as probable human carcinogenic (i.e., Glyphosate, Malathion). In terms of pesticide storage, 40% of farmers said that they did not store pesticides in a separate room after purchasing or using them. The empty containers were buried or burnt by half of the responders, while the remainder were thrown at the edge of fields or in public dumps. Although the participants were aware of the negative effects on their own health and on the environment caused by the application of pesticides in use, the protection measures by individual equipment were insufficient. A canonical analysis indicates that these behaviors were influenced by the farming experience, the benefit of the agricultural council services, the follow-up of training, and the education level. These variables are important factors in explaining and understanding the dangers to both the environment and health caused by pesticides. The most recorded likely consequences of pesticide exposure were visual impairment (46%), followed by dizziness (44.3%), headache (39.4%), and excessive sweating (34.4%), and 30.2% of participants identified consequent respiratory problems. Extension services targeted at safety and protection measures should be developed and accompanied by educational programs to put farmers' perceptions into practice and encourage them to adopt healthy and environmentally friendly behaviors.

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.

A Study of Associations Between Plasma Metformin Concentration, Lactic Acidosis, and Mortality in an Emergency Hospitalization Context.

OBJECTIVES: To determine the plasma metformin concentration threshold associated with lactic acidosis and analyze the outcome in metformin-treated patients with lactic acidosis hospitalized in an emergency context. DESIGN: A retrospective, observational, single-center study. SETTING: Emergency department and ICUs at Amiens University Hospital (Amiens, France). PATIENTS: All consecutive patients with data on arterial lactate and pH up to 12 hours before or after a plasma metformin assay within 24 hours of admission, over a 9.7-year period. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The study population consisted of 194 metformin-treated diabetic patients (median age: 68.6; males: 113 [58.2%]); 163 (84%) had acute kidney injury, which was associated variously with dehydration (45.4%), sepsis (41.1%), cardiogenic shock (20.9%), and diabetic ketoacidosis (16%). Eighty-seven patients (44.8%) had lactic acidosis defined as an arterial blood pH less than 7.35 and a lactate concentration greater than or equal to 4 mM, and 38 of them (43.7%) died in the ICU. A receiver operating characteristic curve analysis showed that a metformin concentration threshold of 9.9 mg/L was significantly associated with the occurrence of lactic acidosis (specificity: 92.9%; sensitivity: 67.1%; area under the receiver operating characteristic curve: 0.83; p < 0.0001). Among lactic acidosis-positive patients, however, in-ICU death was less frequent when the metformin concentration was greater than or equal to 9.9 mg/L (33.9% vs 61.3% for < 9.9 mg/L; p = 0.0252). After adjustment for the Simplified Acute Physiology Score II, in-ICU death was positively associated with prothrombin activity less than 70% and negatively associated with the initiation of renal replacement therapy at admission. CONCLUSIONS: In metformin-treated patients admitted in an emergency context, a plasma metformin concentration greater than or equal to 9.9 mg/L was strongly associated with the presence of lactic acidosis. This threshold may assist with the delicate decision of whether or not to initiate renal replacement therapy. Indeed, the outcome of lactic acidosis might depend on the prompt initiation of renal replacement therapy-especially when liver failure reduces lactate elimination.

How to interpret an estimated glomerular filtration rate (eGFR) in 2020?

Chronic kidney disease (CKD) is defined as abnormalities of kidney structure and function proven to be chronic. The prevalence of CKD in the majority of studies is 10%-16%, neglecting the chronicity character. Jonsson et al., in a nationwide study defining CKD adhering strictly to Kidney Disease: Improving Global Outcomes (KDIGO) criteria, found a clearly lower prevalence of CKD (6%). This indicated that to obtain a correct CKD prevalence, one should start by correctly applying the KDIGO guidelines.

An overview of glucagon-like peptide-1 receptor agonists for the treatment of metabolic syndrome: A drug repositioning.

Metabolic syndrome (MetS) is a clustering of several cardiovascular risk factors that include: obesity, dyslipidemia, hypertension and high blood glucose, and often requires multidrug pharmacological interventions. The management of MetS therefore requires high healthcare cost, and can result in poor drug treatment compliance. Hence drug therapies that have pleiotropic beneficial effects may be of value. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are the newest anti-diabetic drugs that mimic incretin effects in the body. They appear to be safe and well tolerable. Herein, the pharmacology of GLP-1RAs, their side effects, drug interactions and their effects in MetS is assessed. We conducted a Google Scholar, PubMed, Scopus, and Web of Science search since 2010 to identify publications related to the use of GLP-1RAs in treating component features of the MetS. Keywords used for the search were: GLP-1 receptor agonist, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, MetS, obesity, triglyceride, cholesterol, lipid, hypercholesterolemia hyperlipidemia, atherosclerosis, hypertension, blood pressure, hyperglycemia, hypoglycemia and blood glucose. According to the gathered data, GLP-1RAs appear safe and well tolerated. Pre-clinical and clinical studies have evaluated the lipid-lowering, anti-atherosclerotic, anti-hypertensive and anti-diabetic effects of this class of drugs. Some these effects are related to a reduction in food-seeking behavior, an increase in atrial natriuretic peptide level and hence vascular relaxation and natriuresis, and an increase of pancreas ß-cell mass and protection against glucotoxicity. Collectively, this review indicates that there may be some value in GLP-1RAs repositioning to manage MetS risk factors beyond their anti-diabetic effects.

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.

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.

Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder.

Chronic kidney disease (CKD) causes dysregulation of mineral metabolism, vascular calcification and renal osteodystrophy, an entity called 'CKD-Mineral and Bone Disorder' (CKD-MBD). Here we determine whether metformin, an anti-diabetic drug, exerts favorable effects on progressive, severe CKD and concomitant mineral metabolism disturbances. Rats with CKD-MBD, induced by a 0.25% adenine diet for eight weeks, were treated with 200 mg/kg/day metformin or vehicle from one week after CKD induction onward. Severe, stable CKD along with marked hyperphosphatemia and hypocalcemia developed in these rats which led to arterial calcification and high bone turnover disease. Metformin protected from development toward severe CKD. Metformin-treated rats did not develop hyperphosphatemia or hypocalcemia and this prevented the development of vascular calcification and inhibited the progression toward high bone turnover disease. Kidneys of the metformin group showed significantly less cellular infiltration, fibrosis and inflammation. To study a possible direct effect of metformin on the development of vascular calcification, independent of its effect on renal function, metformin (200 mg/kg/day) or vehicle was dosed for ten weeks to rats with warfarin-induced vascular calcification. The drug did not reduce aorta or small vessel calcification in this animal model. Thus, metformin protected against the development of severe CKD and preserved calcium phosphorus homeostasis. As a result of its beneficial impact on renal function, associated comorbidities such as vascular calcification and high bone turnover disease were also prevented.

Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4.

OBJECTIVE: This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies. RESEARCH DESIGN AND METHODS: Three complementary studies were performed: 1) a dose-finding study in CKD stages 1-5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase; 2) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA1c concentrations monitored monthly; and 3) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4. RESULTS: First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning [qam] +1 g in the evening [qpm]) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA1c levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups. CONCLUSIONS: Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD.