Risk factors for reduced glomerular filtration rate in a Nicaraguan community affected by Mesoamerican nephropathy.

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 <60mL/min/1.73m2 and controls were individuals with those >90mL/min/1.73m2, 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 <60mL/min/1.73m2 was 9.8% among women and 41.9% among men (male to female ratio = 4.3, p<0.0001). Proteinuria =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.

An altered redox balance mediates the hypersensitivity of Cockayne syndrome primary fibroblasts to oxidative stress.

Cockayne syndrome (CS) is a rare hereditary multisystem disease characterized by neurological and development impairment, and premature aging. Cockayne syndrome cells are hypersensitive to oxidative stress, but the molecular mechanisms involved remain unresolved. Here we provide the first evidence that primary fibroblasts derived from patients with CS-A and CS-B present an altered redox balance with increased steady-state levels of intracellular reactive oxygen species (ROS) and basal and induced DNA oxidative damage, loss of the mitochondrial membrane potential, and a significant decrease in the rate of basal oxidative phosphorylation. The Na/K-ATPase, a relevant target of oxidative stress, is also affected with reduced transcription in CS fibroblasts and normal protein levels restored upon complementation with wild-type genes. High-resolution magnetic resonance spectroscopy revealed a significantly perturbed metabolic profile in CS-A and CS-B primary fibroblasts compared with normal cells in agreement with increased oxidative stress and alterations in cell bioenergetics. The affected processes include oxidative metabolism, glycolysis, choline phospholipid metabolism, and osmoregulation. The alterations in intracellular ROS content, oxidative DNA damage, and metabolic profile were partially rescued by the addition of an antioxidant in the culture medium suggesting that the continuous oxidative stress that characterizes CS cells plays a causative role in the underlying pathophysiology. The changes of oxidative and energy metabolism offer a clue for the clinical features of patients with CS and provide novel tools valuable for both diagnosis and therapy.

Cell type and DNA damage specific response of human skin cells to environmental agents.

The epidermis has evolved to provide a barrier against the environment, which is essential for survival. This barrier is constituted and continuously regenerated by terminally differentiating keratinocytes. Here, we summarize the main features of the response to UVB and oxidizing agents of human keratinocytes and compare it with that of fibroblasts. Keratinocytes are more resistant to the lethal effects of UVB than fibroblasts and remove cyclobutane pyrimidine dimers (CPD) more efficiently than fibroblasts. UV photoproducts are repaired by the nucleotide excision repair (NER) system by two distinct sub-pathways: global genome repair (GGR) that repairs lesions on the genome overall, and transcription coupled repair (TCR) that operates on transcribed sequences of active genes. By using NER-defective cells we demonstrated that the improved repair of UVB damage by keratinocytes is due to a more efficient GGR. A defect in TCR was associated with a strong apoptotic response in fibroblasts but not in keratinocytes, whereas a defect in GGR had no effect on the apoptotic response of either cell type. We speculate that the persistence of CPD in the transcribed sequences triggers apoptosis in fibroblasts but not in keratinocytes where GGR operates as back-up system to remove transcription-blocking lesions. As observed for UVB, keratinocytes are also more resistant to the lethal effects of oxidizing agents than fibroblasts. We show that keratinocytes are characterized by a strong anti-oxidant capacity and a higher susceptibility to reactive oxygen species (ROS)-induced apoptosis than fibroblasts. All together these results provide a clear evidence that the response to environmental agents is strongly affected by the type of damage as well as by the cellular background.