Kidney Disease

Jayasumana et al., 2014

Channa Jayasumana, Sarath Gunatilake, and Priyantha Senanayake, “Glyphosate, Hard Water and Nephrotoxic Metals: Are They the Culprits Behind the Epidemic of Chronic Kidney Disease of Unknown Etiology in Sri Lanka?,” International Journal of Environmental Research and Public Health, 2014,  11, DOI:10.3390/IJERPH 110202125.


The current chronic kidney disease epidemic, the major health issue in the rice paddy farming areas in Sri Lanka has been the subject of many scientific and political debates over the last decade. Although there is no agreement among scientists about the etiology of the disease, a majority of them has concluded that this is a toxic nephropathy. None of the hypotheses put forward so far could explain coherently the totality of clinical, biochemical, histopathological findings, and the unique geographical distribution of the disease and its appearance in the mid-1990s. A strong association between the consumption of hard water and the occurrence of this special kidney disease has been observed, but the relationship has not been explained consistently. Here, we have hypothesized the association of using glyphosate, the most widely used herbicide in the disease endemic area and its unique metal chelating properties. The possible role played by glyphosate-metal complexes in this epidemic has not been given any serious consideration by investigators for the last two decades. Furthermore, it may explain similar kidney disease epidemics observed in Andra Pradesh (India) and Central America. Although glyphosate alone does not cause an epidemic of chronic kidney disease, it seems to have acquired the ability to destroy the renal tissues of thousands of farmers when it forms complexes with a localized geo environmental factor (hardness) and nephrotoxic metals.   FULL TEXT

Jayasumana et al., 2015

Channa Jayasumana, Sarath Gunatilake, and Sisira Siribaddana, “Simultaneous exposure to multiple heavy metals and glyphosate may contribute to Sri Lankan agricultural nephropathy,” BMC Nephrology, 2015, 16:103, DOI 10.1186/s12882-015-0109-2.


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).

CONCLUSTIONS: 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.  FULL TEXT

Lebov et al., 2015

Jill F. Lebov, MSPH, PhD, Lawrence S. Engel, PhD, David Richardson, PhD, Susan L. Hogan, PhD, Jane A. Hoppin, ScD, and Dale P. Sandler, PhD, “Pesticide use and risk of end-stage renal disease among licensed pesticide applicators in the Agricultural Health Study,” Occupational and Environmental Medicine, 2016, 7, DOI: 10.1136/oemed-2014-102615


OBJECTIVES: Experimental studies suggest a relationship between pesticide exposure and renal impairment, but epidemiological evidence is limited. We evaluated the association between exposure to 41 specific pesticides and end-stage renal disease (ESRD) incidence in the Agricultural Health Study (AHS), a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina.

METHODS: Via linkage to the United States Renal Data System, we identified 320 ESRD cases diagnosed between enrollment (1993-1997) and December 2011 among 55,580 male licensed pesticide applicators. Participants provided pesticide use information via self-administered questionnaires. Lifetime pesticide use was defined as the product of duration and frequency of use and then modified by an intensity factor to account for differences in pesticide application practices. Cox proportional hazards models, adjusted for age and state, were used to estimate associations between ESRD and: 1) ordinal categories of intensity-weighted lifetime use of 41 pesticides, 2) poisoning and high-level pesticide exposures, and 3) pesticide exposure resulting in a medical visit or hospitalization.

RESULTS: Positive exposure-response trends were observed for the herbicides alachlor, atrazine, metolachlor, paraquat, and pendimethalin, and the insecticide chlordane. More than one medical visit due to pesticide use (HR = 2.13; 95% CI: 1.17, 3.89) and hospitalization due to pesticide use (HR = 3.05; 95% CI: 1.67, 5.58) were significantly associated with ESRD.

CONCLUSIONS: Our findings support an association between ESRD and chronic exposure to specific pesticides and suggest pesticide exposures resulting in medical visits may increase the risk of ESRD. FULL TEXT

Ma et. al, 2014

Junguo Ma, Yanzhen Bu, Xiaoyu Li, “Immunological and histopathological responses of the kidney of common carp (Cyprinus carpio L.) sublethally exposed to glyphosate,” Environmental Toxicology and Pharmacology, 2014, 39: 1-8, DOI: 10.1016/j.etap.2014.11.004.


Glyphosate is a broad-spectrum herbicide frequently used world widely in agricultural and non-agricultural areas to control unwanted plants. Health risk of chronic and subchronic exposure of glyphosate on animals and humans has received increasing attention in recent years. The aim of this study was to evaluate the effects of glyphosate on the immunoglobulin M (IgM), complement C3 (C3), and lysozyme (LYZ) in the kidney of common carp exposed to 52.08 or 104.15mg L−1 of glyphosate for 168h. The results showed that the transcriptions of IgM, C3, or LYZ were altered due to glyphosate-exposure, for example, IgM and C3 initially increased at 24h later it decreased (except for a increase of C3 in higher dose group at 24h) while the expression of G-type LYZ were not affected at 24h, then increased at 72h, but decreased at the end of test, however C-type LYZ expression was initially up-regulated (24–72h) but down-regulated at the end of exposure (168h). However, glyphosate-exposure generally decreased the contents of IgM and C3 or inhibited LYZ activity in the kidney of common carp. In addition, glyphosate-exposure also caused remarkable histopathological damage, mainly including vacuolization of the renal parenchyma and intumescence of the renaltubule in fish kidney. The results ofthis study indicate that glyphosate causes immunotoxicity on common carp via suppressing the expressions of IgM, C3, and LYZ and also via damaging the fish kidney.  FULL TEXT

Manikkam et al., 2012c

Mohan Manikkam, Rebecca Tracey, Carlos Guerrero-Bosagna, Michael K. Skinner , “Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations,” PLoS ONE, 2012, 7:9, DOI: 10.1371/journal.pone.0046249.


Environmental compounds can promote epigenetic transgenerational inheritance of adult-onset disease in subsequent generations following ancestral exposure during fetal gonadal sex determination. The current study examined the ability of dioxin (2,3,7,8-tetrachlorodibenzo[p]dioxin, TCDD) to promote epigenetic transgenerational inheritance of disease and DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to dioxin during fetal day 8 to 14 and adult-onset disease was evaluated in F1 and F3 generation rats. The incidences of total disease and multiple disease increased in F1 and F3 generations. Prostate disease, ovarian primordial follicle loss and polycystic ovary disease were increased in F1 generation dioxin lineage. Kidney disease in males, pubertal abnormalities in females, ovarian primordial follicle loss and polycystic ovary disease were increased in F3 generation dioxin lineage animals. Analysis of the F3 generation sperm epigenome identified 50 differentially DNA methylated regions (DMR) in gene promoters. These DMR provide potential epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Observations demonstrate dioxin exposure of a gestating female promotes epigenetic transgenerational inheritance of adult onset disease and sperm epimutations.  FULL TEXT

Manikkam et al., 2014

Mohan Manikkam, M. Muksitul Haque, Carlos Guerrero-Bosagna, Eric E. Nilsson, Michael K. Skinner , “Pesticide Methoxychlor Promotes the Epigenetic Transgenerational Inheritance of Adult-Onset Disease through the Female Germline,” PLoS ONE, 2014, 9:7, DOI: 10.371/JOURNAL.PONE.0102091.


Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.  FULL TEXT

Mesnage et al., 2015b

Robin Mesnage, Matthew Arno, Manuela Costanzo, Manuela Malatesta, Gilles-Eric Séralini and Michael N. Antoniou, “Transcriptome profile analysis reflects rat liver and kidney damage following chronic ultra-low dose Roundup exposure,” Environmental Health, 2015, 14:70, DOI 10.1186/s12940-015-0056-1.


BACKGROUND:  Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. Converging evidence suggests that GBH, such as Roundup, pose a particular health risk to liver and kidneys although low environmentally relevant doses have not been examined. To address this issue, a 2-year study in rats administering 0.1 ppb Roundup (50 ng/L glyphosate equivalent) via drinking water (giving a daily intake of 4 ng/kg bw/day of glyphosate) was conducted. A marked increased incidence of anatomorphological and blood/urine biochemical changes was indicative of liver and kidney structure and functional pathology. In order to confirm these findings we have conducted a transcriptome microarray analysis of the liver and kidneys from these same animals.

RESULTS: The expression of 4224 and 4447 transcript clusters (a group of probes corresponding to a known or putative gene) were found to be altered respectively in liver and kidney (p < 0.01, q < 0.08). Changes in gene expression varied from −3.5 to 3.7 fold in liver and from −4.3 to 5.3 in kidneys. Among the 1319 transcript clusters whose expression was altered in both tissues, ontological enrichment in 3 functional categories among 868 genes were found. First, genes involved in mRNA splicing and small nucleolar RNA were mostly upregulated, suggesting disruption of normal spliceosome activity. Electron microscopic analysis of hepatocytes confirmed nucleolar structural disruption. Second, genes controlling chromatin structure (especially histone-lysine N-methyltransferases) were mostly upregulated. Third, genes related to respiratory chain complex I and the tricarboxylic acid cycle were mostly downregulated. Pathway analysis suggests a modulation of the mTOR and phosphatidylinositol signalling pathways. Gene disturbances associated with the chronic administration of ultra-low dose Roundup reflect a liver and kidney lipotoxic condition and increased cellular growth that may be linked with regeneration in response to toxic effects causing damage to tissues. Observed alterations in gene expression were consistent with fibrosis, necrosis, phospholipidosis, mitochondrial membrane dysfunction and ischemia, which correlate with and thus confirm observations of pathology made at an anatomical, histological and biochemical level.

CONCLUSION: Our results suggest that chronic exposure to a GBH in an established laboratory animal toxicity model system at an ultra-low, environmental dose can result in liver and kidney damage with potential significant health implications for animal and human populations.  FULL TEXT

Raines et al., 2014

Nathan Raines MPH, Marvin González MD MS, Christina Wyatt MD MS, Mark Kurzrok, Christopher Pool, Tiziana Lemma, Ilana Weiss MPH, Carlos Marín, Valerio Prado, Eugenia Marcas, Karina Mayorga, Jean Franco Morales, Aurora Aragón MD PhD, Perry Sheffield MD MPH, “Risk Factors for Reduced Glomerular Filtration Rate in a Nicaraguan Community Affected by Mesoamerican Nephropathy,” MEDICC Review, 2014, 16:2.


INTRODUCTION: Mesoamerican nephropathy, also known as chronic kidney disease of unknown etiology, is widespread in Pacific coastal Central America. The cause of the epidemic is unknown, but the disease may be linked to multiple factors, including diet as well as environmental and occupational exposures. As many as 50% of men in some communities have Mesoamerican nephropathy.

OBJECTIVE: Describe prevalence of reduced glomerular filtration rate in a region of Nicaragua suspected to harbor high rates of Mesoamerican nephropathy; and investigate potential risk factors for such reduction associated with agricultural work (such as pesticide exposure and specific agricultural tasks associated with increased heat stress); sugar consumption; and traditional factors such as age, sex, diabetes, hypertension and nephrotoxic medication use.

METHODS: This study uses a cross-sectional design with nested case-control analysis. Cases were individuals with estimated glomerular filtration rates of <60 mL/min/1.73 m2 and controls were individuals with those >90mL/min/1.73 m2 , estimated using serum creatinine. Data on nutrition, past medical history, medication and substance use, and agricultural behaviors and exposures were collected using medical questionnaires from June through August, 2012. Venous blood and urine samples were collected to assess hemoglobin A1c, and dipstick proteinuria, respectively; anthropometry and blood pressure measurements were made using standard techniques. Analyses were conducted using chi square, and univariate and multiple logistic regression.

RESULTS: Of 424 individuals in the study, 151 had an occupational history in agriculture. Prevalence of glomerular filtration rate <60 mL/ min/1.73 m2 was 9.8% among women and 41.9% among men (male to female ratio = 4.3, p<0.0001). Proteinuria > or equal to 300 mg/dL was observed in <10% of participants with decreased glomerular filtration rate. Hemoglobin A1c and use of NSAIDs were not associated with decreased glomerular filtration rate. Although systolic and diastolic blood pressure was higher among participants with decreased glomerular filtration rate (p <0.001), hypertension was uncommon. Significant agricultural risk factors for reduced glomerular filtration rate included increased lifetime days cutting sugarcane during the dry season (OR 5.86, 95% CI 2.45–14.01), nondeliberate pesticide inhalation (OR 3.31, 95% CI 1.32–8.31), and sugarcane chewing (OR 3.24, 95% CI 1.39–7.58).

CONCLUSIONS: Our findings demonstrate a high prevalence of chronic kidney disease not linked to traditional risk factors, and suggest it may be associated instead with occupational exposure to heat stress in conjunction with pesticide inhalation, sugarcane chewing and sugar intake during the workday.  FULL TEXT

Séralini et al., 2014

Gilles-Eric Séralini, Emilie Clair, Robin Mesnage, Steeve Gress, Nicolas Defarge, Manuela Malatesta, Didier Hennequin and Joël Spiroux de Vendômois, “Republished study: long-term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize,” Environmental Sciences Europe, Bridging Science and Regulation at the Regional and European Level, 2014, 26:14. DOI: 10.1186/s12302-014-0014-5


BACKGROUND: The health effects of a Roundup-tolerant NK603 genetically modified (GM) maize(from 11% in the diet), cultivated with or without Roundup application and Roundup alone (from 0.1 ppb of the full pesticide containing glyphosate and adjuvants) in drinking water, were evaluated for 2 years in rats. This study constitutes a follow-up investigation of a 90-day feeding study conducted by Monsanto in order to obtain commercial release of this GMO, employing the same rat strain and analyzing biochemical parameters on the same number of animals per group as our investigation. Our research represents the first chronic study on these substances, in which all observations including tumors are reported chronologically. Thus, it was not designed as a carcinogenicity study. We report the major findings with 34 organs observed and 56 parameters analyzed at 11 time points for most organs.

RESULTS: Biochemical analyses confirmed very significant chronic kidney deficiencies, for all treatments and both sexes; 76% of the altered parameters were kidney-related.In treated males, liver congestions and necrosis were 2.5 to 5.5 times higher.Marked and severe nephropathies were also generally 1.3 to 2.3 times greater. In females, all treatment groups showed a two- to threefold increase in mortality,and deaths were earlier. This difference was also evident in three male groups fed with GM maize. All results were hormone- and sex-dependent, and the pathological profiles were comparable. Females developed large mammary tumors more frequently and before controls; the pituitary was the second most disabled organ; the sex hormonal balance was modified by consumption of GM maize and Roundup treatments.Males presented up to four times more large palpable tumors starting 600 days earlier than in the control group, in which only one tumor was noted. These results may be explained by not only the non-linear endocrine-disrupting effects of Roundup but also by the over expression of the EPSPS transgene or other mutational effects in the GM maize and their metabolic consequences.

CONCLUSION: Our findings imply that long-term (2 year) feeding trials need to be conducted to thoroughly evaluate the safety of GM foods and pesticides in their full commercial formulations.  FULL TEXT

Skinner et al., 2013b

Skinner MK, Manikkam M, Tracey R, Guerrero-Bosagna C, Haque M, Nilsson EE, “Ancestral dichlorodiphenyltrichloroethane (DDT) exposure promotes epigenetic transgenerational inheritance of obesity,” BMC Medicine, 2013, 11:228, DOI: 10.1186/1741-7015-11-228.


BACKGROUND: Ancestral environmental exposures to a variety of environmental factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The present work examined the potential transgenerational actions of the insecticide dichlorodiphenyltrichloroethane (DDT) on obesity and associated disease.

METHODS: Outbred gestating female rats were transiently exposed to a vehicle control or DDT and the F1 generation offspring bred to generate the F2 generation and F2 generation bred to generate the F3 generation. The F1 and F3 generation control and DDT lineage rats were aged and various pathologies investigated. The F3 generation male sperm were collected to investigate methylation between the control and DDT lineage male sperm.

RESULTS: The F1 generation offspring (directly exposed as a fetus) derived from the F0 generation exposed gestating female rats were not found to develop obesity. The F1 generation DDT lineage animals did develop kidney disease, prostate disease, ovary disease and tumor development as adults. Interestingly, the F3 generation (great grand-offspring) had over 50% of males and females develop obesity. Several transgenerational diseases previously shown to be associated with metabolic syndrome and obesity were observed in the testis, ovary and kidney. The transgenerational transmission of disease was through both female (egg) and male (sperm) germlines. F3 generation sperm epimutations, differential DNA methylation regions (DMR), induced by DDT were identified. A number of the genes associated with the DMR have previously been shown to be associated with obesity.

CONCLUSIONS: Observations indicate ancestral exposure to DDT can promote obesity and associated disease transgenerationally. The etiology of disease such as obesity may be in part due to environmentally induced epigenetic transgenerational inheritance.   FULL TEXT