Exposome and Metabolome Analysis of Sugarcane Workers Reveals Predictors of Kidney Injury.

Introduction: Sugarcane workers are exposed to potentially hazardous agrochemicals, including pesticides, heavy metals, and silica. Such occupational exposures present health risks and have been implicated in a high rate of kidney disease seen in these workers. Methods: To investigate potential biomarkers and mechanisms that could explain chronic kidney disease (CKD) among this worker population, paired urine samples were collected from sugarcane cutters at the beginning and end of a harvest season in Guatemala. Workers were then separated into 2 groups, namely those with or without kidney function decline (KFD) across the harvest season. Urine samples from these 2 groups underwent elemental analysis and untargeted metabolomics. Results: Urine profiles demonstrated increases in silicon, certain pesticides, and phosphorus levels in all workers, whereas heavy metals remained low. The KFD group had a reduction in estimated glomerular filtration rate (eGFR) across the harvest season; however, kidney injury marker 1 did not significantly change. Cross-harvest metabolomic analysis found trends of fatty acid accumulation, perturbed amino acid metabolism, presence of pesticides, and other known signs of impaired kidney function. Conclusion: Silica and certain pesticides were significantly elevated in the urine of sugarcane workers with or without KFD. Future work should determine whether long-term occupational exposure to silica and pesticides across multiple seasons contributes to CKD in these workers. Overall, these results confirmed that multiple exposures are occurring in sugarcane workers and may provide insight into early warning signs of kidney injury and may help explain the increased incidence of CKD among agricultural workers.

Health burden of sugarcane burning on agricultural workers and nearby communities.

Sugarcane is the most widely cultivated crop in the world, with equatorial developing nations performing most of this agriculture. Burning sugarcane is a common practice to facilitate harvest, producing extremely high volumes of respirable particulate matter in the process. These emissions are known to have deleterious effects on agricultural workers and nearby communities, but the extent of this exposure and potential toxicity remain poorly characterized. As the epidemicof chronic kidney disease of an unknown etiology (CKDu) and its associated mortality continue to increase along with respiratory distress, there is an urgent need to investigate the causes, determine viable interventions to mitigate disease andimprove outcomes for groups experiencing disproportionate impact. The goal of this review is to establish the state of available literature, summarize what is known in terms of human health risk, and provide recommendations for what areas should be prioritized in research.

Intranasal Administration of Sugarcane Ash Causes Chronic Kidney Disease in Rats.

Background. Silica nanoparticles found in sugarcane ash have been postulated to be a toxicant contributing to chronic kidney disease of unknown etiology (CKDu). However, while the administration of manufactured silica nanoparticles is known to cause chronic tubulointerstitial disease in rats, the effect of administering sugarcane ash on kidney pathology remains unknown. Here we investigate whether sugarcane ash can induce CKD in rats. Methods. Sugarcane ash was administered for 13 weeks into the nares of rats (5 mg/day for 5d/week), and blood, urine and kidney tissues were collected at 13 weeks (at the end of ash administration) and in a separate group of rats at 24 weeks (11 weeks after stopping ash administration). Kidney histology was evaluated, and inflammation and fibrosis (collagen deposition) measured. Results. Sugarcane ash exposure led to the accumulation of silica in the kidneys, lungs, liver and spleen of rats. Mild proteinuria developed although renal function was largely maintained. However, biopsies showed focal glomeruli with segmental glomerulosclerosis, and tubulointerstitial inflammation and fibrosis that tended to worsen even after the ash administration had been stopped. Staining for the lysosomal marker, LAMP-1, showed decreased staining in ash administered rats consistent with lysosomal activation. Conclusion. Sugarcane ash containing silica nanoparticles can cause CKD in rats.

Sugarcane ash and sugarcane ash-derived silica nanoparticles alter cellular metabolism in human proximal tubular kidney cells.

Multiple epidemics of chronic kidney disease of an unknown etiology (CKDu) have emerged in agricultural communities around the world. Many factors have been posited as potential contributors, but a primary cause has yet to be identified and the disease is considered likely multifactorial. Sugarcane workers are largely impacted by disease leading to the hypothesis that exposure to sugarcane ash produced during the burning and harvest of sugarcane could contribute to CKDu. Estimated exposure levels of particles under 10 µm (PM10) have been found to be exceptionally high during this process, exceeding 100 µg/m3 during sugarcane cutting and averaging ∼1800 µg/m3 during pre-harvest burns. Sugarcane stalks consist of ∼80% amorphous silica and generate nano-sized silica particles (∼200 nm) following burning. A human proximal convoluted tubule (PCT) cell line was subjected to treatments ranging in concentration from 0.025 µg/mL to 25 µg/mL of sugarcane ash, desilicated sugarcane ash, sugarcane ash-derived silica nanoparticles (SAD SiNPs) or manufactured pristine 200 nm silica nanoparticles. The combination of heat stress and sugarcane ash exposure on PCT cell responses was also assessed. Following 6-48 h of exposure, mitochondrial activity and viability were found to be significantly reduced when exposed to SAD SiNPs at concentrations 2.5 µg/mL or higher. Oxygen consumption rate (OCR) and pH changes suggested significant alteration to cellular metabolism across treatments as early as 6 h following exposure. SAD SiNPs were found to inhibit mitochondrial function, reduce ATP generation, increase reliance on glycolysis, and reduce glycolytic reserve. Metabolomic analysis revealed several cellular energetics pathways (e.g., fatty acid metabolism, glycolysis, and TCA cycle) are significantly altered across ash-based treatments. Heat stress did not influence these responses. Such changes indicate that exposure to sugarcane ash and its derivatives can promote mitochondrial dysfunction and disrupt metabolic activity of human PCT cells.

Aminoaciduria and metabolic dysregulation during diabetic ketoacidosis: Results from the diabetic kidney alarm (DKA) study.

OBJECTIVE: We examined changes in the excretion of various amino acids and in glycolysis and ketogenesis-related metabolites, during and after diabetic ketoacidosis (DKA) diagnosis, in youth with known or new onset type 1 diabetes (T1D). METHODS: Urine samples were collected from 40 youth with DKA (52% boys, mean age 11 ± 4 years, venous pH 7.2 ± 0.1, blood glucose 451 ± 163 mg/dL) at 3 time points: 0-8 h and 12-24 h after starting an insulin infusion, and 3 months after hospital discharge. Mixed-effects models evaluated the changes in amino acids and other metabolites in the urine. RESULTS: Concentrations of urine histidine, threonine, tryptophan, and leucine per creatinine were highest at 0-8 h (148.8 ± 23.5, 59.5 ± 12.3, 15.4 ± 1.4, and 24.5 ± 2.4% of urine creatinine, respectively), and significantly decreased over 3 months (p = 0.028, p = 0.027, p = 0.019, and p < 0.0001, respectively). Urine histidine, threonine, tryptophan, and leucine per urine creatinine decreased by 10.6 ± 19.2, 0.7 ± 0.9, 1.3 ± 0.9, and 0.5 ± 0.3-fold, respectively, between 0 and 8 h and 3 months. CONCLUSIONS: In our study, DKA was associated with profound aminoaciduria, suggestive of proximal tubular dysfunction analogous to Fanconi syndrome.

Inhaled silica nanoparticles cause chronic kidney disease in rats.

Silica nanoparticles (SiNPs) released during the burning of sugarcane have been postulated to have a role in chronic kidney disease of unknown etiology. We tested the hypothesis that pristine SiNPs of the size present in sugarcane might cause chronic kidney injury when administered through the lung in rats. We administered 200- or 300-nm amorphous SiNPs twice weekly (4 mg/dose), or vehicle by oropharyngeal aspiration for 13 wk to rats followed by euthanasia after an additional 13 wk (26 wk total). Tissues were evaluated for the presence of SiNPs and evidence of histological injury. Both sizes of SiNPs caused kidney damage, with early tubular injury and inflammation (at week 13) that continued to inflammation and chronic fibrosis at week 26 despite discontinuation of the SiNP administration. Both sizes of SiNPs caused local inflammation in the lung and kidney and were detected in the serum and urine at week 13, and the 200-nm particles were also localized to the kidney with no evidence of retention of the 300-nm particles. At week 26, there was some clearance of the 200-nm silica from the kidneys, and urinary levels of SiNPs were reduced but still significant in both 200- and 300 nm-exposed rats. In conclusion, inhaled SiNPs cause chronic kidney injury that progresses despite stopping the SiNP administration. These findings support the hypothesis that human exposure to amorphous silica nanoparticles found in burned sugarcane fields could have a participatory role in chronic kidney disease of unknown etiology.NEW & NOTEWORTHY Inhalation of silica nanoparticles (SiNPs) released during the burning of sugarcane has been postulated to have a role in chronic kidney disease of unknown etiology (CKDu). We administered 200- and 300-nm amorphous SiNPs to rats by aspiration and observed kidney damage with tubular injury and inflammation that persisted even after stopping the SiNP exposure. These findings support the hypothesis that human exposure to SiNPs found in sugarcane ash could have a participatory role CKDu.

Tubular injury in diabetic ketoacidosis: Results from the diabetic kidney alarm study.

OBJECTIVE: Glomerular injury is a recognized complication of diabetic ketoacidosis (DKA), yet the tubular lesions are poorly understood. The aim of this prospective study was to evaluate the presence and reversibility of tubular injury during DKA in children with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Blood and urine samples were collected from 40 children with DKA (52% boys, mean age 11 ± 4 years, venous pH 7.2 ± 0.1, glucose 451 ± 163 mg/dL) at three timepoints: 0-8 and 12-24 h after starting insulin, and 3 months after discharge. Mixed-effects models evaluated the changes in tubular injury markers over time (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule 1 [KIM-1], and interleukin 18 [IL-18]). We also evaluated the relationships among the tubular injury biomarkers, copeptin, a vasopressin surrogate, and serum uric acid (SUA). RESULTS: Serum NGAL, KIM-1, and IL-18 were highest at 0-8 h (306.5 ± 45.9 ng/mL, 128.9 ± 10.1 pg/mL, and 564.3 ± 39.2 pg/mL, respectively) and significantly decreased over 3 months (p = 0.03, p = 0.01, and p < 0.001, respectively). There were strong relationships among increases in copeptin and SUA and rises in tubular injury biomarkers. At 0-8 h, participants with acute kidney injury (AKI) [17%] showed significantly higher concentrations of tubular injury markers, copeptin, and SUA. CONCLUSIONS: DKA was characterized by tubular injury, and the degree of injury associated with elevated copeptin and SUA. Tubular injury biomarkers, copeptin and SUA may be able to predict AKI in DKA.

A Novel Treatment for Glomerular Disease: Targeting the Activated Macrophage Folate Receptor with a Trojan Horse Therapy in Rats.

Since activated macrophages express a functional folate receptor ß (FRß), targeting this macrophage population with folate-linked drugs could increase selectivity to treat inflammatory diseases. Using a macrophage-mediated anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN) in WKY rats, we investigated the effect of a novel folic acid-aminopterin (AMT) conjugate (EC2319) designed to intracellularly deliver AMT via the FR. We found that treatment with EC2319 significantly attenuated kidney injury and preserved renal function. Kidney protection with EC2319 was blocked by a folate competitor, indicating that its mechanism of action was specifically FRß-mediated. Notably, treatment with methotrexate (MTX), another folic acid antagonist related to AMT, did not protect from kidney damage. EC2319 reduced glomerular and interstitial macrophage infiltration and decreased M1 macrophage recruitment but not M2 macrophages. The expression of CCL2 and the pro-fibrotic cytokine TGF-ß were also reduced in nephritic glomeruli with EC2319 treatment. In EC2319-treated rats, there was a significant decrease in the deposition of collagens. In nephritic kidneys, FRß was expressed on periglomerular macrophages and macrophages present in the crescents, but its expression was not observed in normal kidneys. These data indicate that selectively targeting the activated macrophage population could represent a novel means for treating anti-GBM GN and other acute crescentic glomerulonephritis.

Osthol Ameliorates Kidney Damage and Metabolic Syndrome Induced by a High-Fat/High-Sugar Diet.

Excessive intake of fructose results in metabolic syndrome (MS) and kidney damage, partly mediated by its metabolism by fructokinase-C or ketohexokinase-C (KHK-C). Osthol has antioxidant properties, is capable of regulating adipogenesis, and inhibits KHK-C activity. Here, we examined the potential protective role of osthol in the development of kidney disease induced by a Western (high-fat/high-sugar) diet. Control rats fed with a high-fat/high-sugar diet were compared with two groups that also received two different doses of osthol (30 mg/kg/d or 40 mg/kg/d body weight BW). A fourth group served as a normal control and received regular chow. At the end of the follow-up, kidney function, metabolic markers, oxidative stress, and lipogenic enzymes were evaluated. The Western diet induced MS (hypertension, hyperglycemia, hypertriglyceridemia, obesity, hyperuricemia), a fall in the glomerular filtration rate, renal tubular damage, and increased oxidative stress in the kidney cortex, with increased expression of lipogenic enzymes and increased kidney KHK expression. Osthol treatment prevented the development of MS and ameliorated kidney damage by inhibiting KHK activity, preventing oxidative stress via nuclear factor erythroid 2-related factor (Nrf2) activation, and reducing renal lipotoxicity. These data suggest that the nutraceutical osthol might be an ancillary therapy to slow the progression of MS and kidney damage induced by a Western diet.

Vasopressin mediates fructose-induced metabolic syndrome by activating the V1b receptor.

Subjects with obesity frequently have elevated serum vasopressin levels, noted by measuring the stable analog, copeptin. Vasopressin acts primarily to reabsorb water via urinary concentration. However, fat is also a source of metabolic water, raising the possibility that vasopressin might have a role in fat accumulation. Fructose has also been reported to stimulate vasopressin. Here, we tested the hypothesis that fructose-induced metabolic syndrome is mediated by vasopressin. Orally administered fructose, glucose, or high-fructose corn syrup increased vasopressin (copeptin) concentrations and was mediated by fructokinase, an enzyme specific for fructose metabolism. Suppressing vasopressin with hydration both prevented and ameliorated fructose-induced metabolic syndrome. The vasopressin effects were mediated by the vasopressin 1b receptor (V1bR), as V1bR-KO mice were completely protected, whereas V1a-KO mice paradoxically showed worse metabolic syndrome. The mechanism is likely mediated in part by de novo expression of V1bR in the liver that amplifies fructokinase expression in response to fructose. Thus, our studies document a role for vasopressin in water conservation via the accumulation of fat as a source of metabolic water. Clinically, they also suggest that increased water intake may be a beneficial way to both prevent or treat metabolic syndrome.

Fluid Intake Restriction Concomitant to Sweetened Beverages Hydration Induce Kidney Damage.

Currently, there is the paradox of low water intake but increased intake of sugar-sweetened beverages (SB) in several populations; those habits are associated with an increased prevalence of metabolic derangements and greater chronic disease mortality. Persistent heat dehydration and increased SB intake stimulate the continued release of vasopressin and overactivation of the polyol-fructokinase pathway, synergizing each other, an effect partially mediated by oxidative stress. The objective of the present study was to evaluate whether water restriction concurrent with SB hydration can cause renal damage by stimulating similar pathways as heat dehydration. Three groups of male Wistar rats (n = 6) were fluid restricted; from 10 am to 12 pm animals could rehydrate with tap water (W), or sweetened beverages, one prepared with 11% of a fructose-glucose combination (SB), or with the noncaloric edulcorant stevia (ST). A normal control group of healthy rats was also studied. The animals were followed for 4 weeks. Markers of dehydration and renal damage were evaluated at the end of the study. Fluid restriction and water hydration mildly increased urine osmolality and induced a 15% fall in CrCl while increased the markers of tubular damage by NAG and KIM-1. Such changes were in association with a mild overexpression of V1a and V2 renal receptors, polyol fructokinase pathway overactivation, and increased renal oxidative stress with reduced expression of antioxidant enzymes. Hydration with SB significantly amplified those alterations, while in stevia hydrated rats, the changes were similar to the ones observed in water hydrated rats. These data suggest that current habits of hydration could be a risk factor in developing kidney damage.

Hyperosmolarity and Increased Serum Sodium Concentration Are Risks for Developing Hypertension Regardless of Salt Intake: A Five-Year Cohort Study in Japan.

The potential contribution of serum osmolarity in the modulation of blood pressure has not been evaluated. This study was done to examine the relationship between hyperosmolarity and hypertension in a five-year longitudinal design. We enrolled 10,157 normotensive subjects without diabetes who developed hypertension subsequently as determined by annual medical examination in St. Luke's International Hospital, Tokyo, between 2004 and 2009. High salt intake was defined as >12 g/day by a self-answered questionnaire and hyperosmolarity was defined as >293 mOsm/L serum osmolarity, calculated using serum sodium, fasting blood glucose, and blood urea nitrogen. Statistical analyses included adjustments for age, gender, body mass index, smoking, drinking alcohol, dyslipidemia, hyperuricemia, and chronic kidney disease. In the patients with normal osmolarity, the group with high salt intake had a higher cumulative incidence of hypertension than the group with normal salt intake (8.4% versus 6.7%, p = 0.023). In contrast, in the patients with high osmolarity, the cumulative incidence of hypertension was similar in the group with high salt intake and in the group with normal salt intake (13.1% versus 12.9%, p = 0.84). The patients with hyperosmolarity had a higher incidence of hypertension over five years compared to that of the normal osmolarity group (p < 0.001). After multiple adjustments, elevated osmolarity was an independent risk for developing hypertension (OR (odds ratio), 1.025; 95% CI (confidence interval), 1.006-1.044), regardless of the amount of salt intake. When analyzed in relation to each element of calculated osmolarity, serum sodium and fasting blood glucose were independent risks for developing hypertension. Our results suggest that hyperosmolarity is a risk for developing hypertension regardless of salt intake.

The Optimal Range of Serum Uric Acid for Cardiometabolic Diseases: A 5-Year Japanese Cohort Study.

The optimal range of serum uric acid (urate) associated with the lowest risk for developing cardiometabolic diseases is unknown in a generally healthy population. This 5-year cohort study is designed to identify the optimal range of serum urate. The data were collected from 13,070 Japanese between ages 30 and 85 at the baseline (2004) from the Center for Preventive Medicine, St. Luke's International Hospital, Tokyo. We evaluated the number of subjects (and prevalence) of those free of the following conditions: hypertension, diabetes, dyslipidemia, and chronic kidney disease (CKD) over 5 years for each 1 mg/dL of serum urate stratified by sex. Furthermore, the odds ratios (ORs) for remaining free of these conditions were calculated with multiple adjustments. Except for truly hypouricemic subjects, having lower serum urate was an independent factor for predicting the absence of hypertension, dyslipidemia, and CKD, but not diabetes. The OR of each 1 mg/dL serum urate decrease as a protective factor for hypertension, dyslipidemia, and CKD was 1.153 (95% confidence interval, 1.068-1.245), 1.164 (1.077-1.258), and 1.226 (1.152-1.306) in men; 1.306 (1.169-1.459), 1.121 (1.022-1.230), and 1.424 (1.311-1.547) in women, respectively. Moreover, comparing serum urate of 3-5 mg/dL in men and 2-4 mg/dL in women, hypouricemia could be a higher risk for developing hypertension (OR: 4.532; 0.943-21.78) and CKD (OR: 4.052; 1.181-13.90) in women, but not in men. The optimal serum urate range associated with the lowest development of cardiometabolic diseases was less than 5 mg/dL for men and 2-4 mg/dL for women, respectively.

A Role for Both V1a and V2 Receptors in Renal Heat Stress Injury Amplified by Rehydration with Fructose.

Chronic vasopressin secretion induced by recurrent mild heat stress exposure is significantly enhanced by limited rehydration with a fructose-containing beverage both in rodents and in humans. Moreover, this effect has been associated with upregulation of the polyol-fructokinase pathway and increased renal oxidative stress. Previously, we have shown that pharmacological inhibition of both V1a and V2 vasopressin receptors with conivaptan improved such renal alterations. The aim of this study was to evaluate the independent contributions of V1a and V2 receptors to the renal damage caused by mild heat stress and limited rehydration with a fructose-containing beverage. Osmotic minipumps were used to deliver either relcovaptan (0.64 mg/day) or tolvaptan (0.25 mg/day) in male Wistar rats for two weeks. Corresponding dilution vehicles were used as controls. To induce dehydration, rats were exposed to mild heat stress (37 °C for 1 h, Monday to Friday). All groups received a 10% fructose solution as a rehydration fluid for 2 h after mild heat stress. For the remainder of the day and on weekends, rats received tap water. The independent blockade of either the V1a or the V2 receptor prevented renal damage, reduced oxidative stress, and decreased plasma cortisol and systemic inflammation. However, the beneficial effects were regulated by different mechanisms. Tolvaptan inhibited polyol-fructokinase pathway overactivation, while relcovaptan prevented upregulation of the renin-angiotensin system and SGK1 expression. These data suggest that both V1a and V2 receptors participate in renal damage caused by heat stress-induced dehydration when fructose-containing beverages are used as rehydration fluids.

Obesity causes renal mitochondrial dysfunction and energy imbalance and accelerates chronic kidney disease in mice.

Obesity and metabolic syndrome are well-known risk factors for chronic kidney disease (CKD); however, less is known about the mechanism(s) by which metabolic syndrome might accelerate kidney disease. We hypothesized that metabolic syndrome should accelerate the development of kidney disease and that it might be associated with alterations in energy metabolism. We studied the pound mouse (which develops early metabolic syndrome due to a leptin receptor deletion) and wild-type littermates and compared the level of renal injury and muscle wasting after equivalent injury with oral adenine. Renal function, histology, and biochemical analyses were performed. The presence of metabolic syndrome was associated with earlier development of renal disease (12 mo) and earlier mortality in pound mice compared with controls. After administration of adenine, kidney disease was worse in pound mice, and this was associated with greater tubular injury with a decrease in kidney mitochondria, lower tissue ATP levels, and worse oxidative stress. Pound mice with similar levels of renal function as adenine-treated wild-type mice also showed worse sarcopenia, with lower tissue ATP and intracellular phosphate levels. In summary, our data demonstrate that obesity and metabolic syndrome accelerate the progression of CKD and worsen CKD-dependent sarcopenia. Both conditions are associated with renal alterations in energy metabolism and lower tissue ATP levels secondary to mitochondrial dysfunction and reduced mitochondrial number.

Increase of core temperature affected the progression of kidney injury by repeated heat stress exposure.

An epidemic of chronic kidney disease of unknown etiology (Mesoamerican nephropathy) has emerged in hot regions of Central America. We have demonstrated that dehydration associated with recurrent heat exposure causes chronic kidney disease in animal models. However, the independent influence of core body temperature on kidney injury has not been explored. In the present study, we tested the hypothesis that kidney injury could be accelerated by increasing body temperature independent of external temperature. Wild-type mice were exposed to heat (39.5°C, 30 min, 2 times daily) with or without the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) for 10 days. Core temperature, renal function, proteinuria, and renal histological and biochemical analyses were performed. Isolated mitochondria markers of oxidative stress were evaluated from kidney tissue. DNP increased body core temperature in response to heat by 1°C (42 vs. 41°C), which was transient. The mild increase in temperature correlated with worsening albuminuria (R = 0.715, P < 001), renal tubular injury, and interstitial infiltration of monocytes/macrophages. Tubular injury was marked in the outer medulla. This was associated with a reduction in kidney tissue ATP levels (nonheated control: 16.71 ± 1.33 nmol/mg and DNP + heat: 13.08 ± 1.12 nmol/mg, P < 0.01), reduced mitochondria, and evidence for mitochondrial oxidative stress. The results of the present study suggest that kidney injury in heat stress is markedly worsened by increasing core temperature. This is consistent with the hypothesis that clinical and subclinical heat stroke may play a role in Mesoamerican nephropathy.

Antioxidant supplements as a novel mean for blocking recurrent heat stress-induced kidney damage following rehydration with fructose-containing beverages.

Recently repeated heat stress and dehydration have been reported to cause oxidative stress and kidney damage that is enhanced by rehydrating with fructose solutions. We hypothesized that antioxidants might provide a novel way to prevent kidney damage. To test this hypothesis, mild heat stress was induced by exposing rats to 37 °C during 1 h in a closed chamber. The supplementation with water-soluble antioxidants (Antiox), ascorbic acid 1% plus N-acetyl cysteine 600 mg/L was done either in the 10% fructose 2 h rehydration fluid immediately after heat stress (Fructose 10% + Antiox), and/or in the tap water (Water + Antiox) for the remainder of the day, or in both fluids. After 4 weeks, control rats exposed to heat with fructose rehydration developed impaired renal function, tubular injury, intrarenal oxidative stress, a reduction in Nrf2-Keap1 antioxidant pathway, stimulation of vasopressin and the intrarenal polyol-fructokinase pathway. In contrast, dosing the antioxidants in the tap water (i.e., before the heat exposure and rehydration with fructose) preserved renal function, prevented renal tubule dysfunction and avoided the increase in systemic blood pressure. These effects were likely due to the amplification of the antioxidant defenses through increased Nrf2 nuclear translocation stimulated by the antioxidants and by the prevention of polyol fructokinase pathway overactivation. More studies to understand the mechanisms implicated in this pathology are warranted as there is recent evidence that they may be operating in humans as well.

Climate Change and the Kidney.

The worldwide increase in temperature has resulted in a marked increase in heat waves (heat extremes) that carries a markedly increased risk for morbidity and mortality. The kidney has a unique role not only in protecting the host from heat and dehydration but also is an important site of heat-associated disease. Here we review the potential impact of global warming and heat extremes on kidney diseases. High temperatures can result in increased core temperatures, dehydration, and blood hyperosmolality. Heatstroke (both clinical and subclinical whole-body hyperthermia) may have a major role in causing both acute kidney disease, leading to increased risk of acute kidney injury from rhabdomyolysis, or heat-induced inflammatory injury to the kidney. Recurrent heat and dehydration can result in chronic kidney disease (CKD) in animals and theoretically plays a role in epidemics of CKD developing in hot regions of the world where workers are exposed to extreme heat. Heat stress and dehydration also has a role in kidney stone formation, and poor hydration habits may increase the risk for recurrent urinary tract infections. The resultant social and economic consequences include disability and loss of productivity and employment. Given the rise in world temperatures, there is a major need to better understand how heat stress can induce kidney disease, how best to provide adequate hydration, and ways to reduce the negative effects of chronic heat exposure.