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Metabolic and Kidney Diseases in the Setting of Climate Change, Shortage, and Survival Factors

† Richard J. Johnson,* Peter Stenvinkel, Thomas Jensen,* Miguel A. Lanaspa,* Carlos Roncal,* ‡ Zhilin Song,* Lise Bankir, and Laura G. Sánchez-Lozada§

*Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado; †Division of Renal Medicine, Department of Clinical Science Intervention and Technology, Karolinska University Hospital, Stockholm, Sweden; ‡Institut National de las Santé et de la Recherche Medicalé UMRS 1138, Centre de Recherche des Cordeliers, Paris, France; and §Laboratory of Renal Physiopathology, Instituto Nacional de Cardiologia Ignacio Chávez, Mexico City, Mexico

ABSTRACT Climate change (global warming) is leading to an increase in heat extremes and epidemics and their relationship to local coupled with increasing water shortage, provides a perfect storm for a new era of temperatures and changing climate, space environmental crises and potentially, new diseases. We use a comparative physio- constraints prevented it from being able to logic approach to show that one of the primary mechanisms by which animals address a more central question on the bi- protect themselves against water shortage is to increase mass as a means for ology of water conservation and how it re- providing metabolic water. Strong evidence suggests that certain hormones lates to disease. Here we review how various (vasopressin), foods (fructose), and metabolic products () function as species protect themselves from dehydra- survival signals to help reduce water loss and store fat (which also provides a source tion, and we identify nutrient, hormonal of metabolic water). These mechanisms are intricately linked with each other and and metabolic pathways triggered by hy- stimulated by dehydration and hyperosmolarity. Although these mechanisms were perosmolarity that link water conservation protective in the setting of low sugar and low salt intake in our past, today, the combination of diets high in fructose and salty foods, increasing temperatures, and with survival. We also discuss how these decreasing available water places these survival signals in overdrive and may be pathways may predict diseases that will accelerating the obesity and diabetes epidemics. The recent discovery of multiple dominate the next millennium. Impor- epidemics of CKD occurring in agricultural workers in hot and humid environments tantly, climate change, heat stress, and may represent harbingers of the detrimental consequences of the combination of water shortage not only will affect kidney climate change and overactivation of survival pathways. disease, but risk for metabolic diseases in- cluding obesity and diabetes. J Am Soc Nephrol 27: 2247–2256, 2016. doi: 10.1681/ASN.2015121314

HOW ANIMALS SURVIVE WATER The 21st century is bringing new chal- moderate water shortage (i.e.,1.0–1.7 m3 SHORTAGE lenges with population expansion, a de- water per person per year), and 10% have crease in natural resources, and climate extreme water shortage (defined as The transition of vertebrates from sea based change. Mean temperatures increased by ,0.5 m3 per person per year), with the pri- to land was associated with many adapta- 0.8°C since 1880, with two thirds of the mary areas affected being Africa, southern tions, but some of the most important were change occurring since 1975, and they and eastern Asia, and the Middle East.4 mechanisms to conserve water, including are projected to increase by 3°C to 4°C Increasing water shortage coupled by the end of the 21st century.1,2 Temper- with climate change increases the risk Published online ahead of print. Publication date atureextremeshavealsoincreasedby75% for dehydration-associated diseases. For available at www.jasn.org. because of climate change.3 Continued example, there is increasing evidence that Correspondence: Dr. Richard J. Johnson, Division population growth and to a lesser extent, climate change may have a role in epi- of Renal Diseases and Hypertension, University of Colorado Denver, 12700 East 19th Avenue, Aurora climate change have also resulted in de- demics of CKD that are occurring among CO 80045. Email: [email protected] 4,5 6 creasing water resources. Today, one workers in hot environments. While this Copyright © 2016 by the American Society of half of the world population suffer latter paper focuses on the sites of these Nephrology

J Am Soc Nephrol 27: 2247–2256, 2016 ISSN : 1046-6673/2708-2247 2247 SPECIAL ARTICLE www.jasn.org ways to store water, minimize water loss, Although ureotelic animals have ob- but when fat is oxidized, water and car- and generate water.7 ligate water loss to help excrete metabolic bon dioxide are released. For every gram wastes, urinary loss is minimized by of fat metabolized, 1.12 ml water is gen- Water Storage urinary concentration, a process largely erated.16 Liver or muscle glycogen also Some terrestrial animals store water in driven by vasopressin (or vasotocin in generates 0.6 ml water per gram of gly- their bladders. The water-holding frog lower vertebrates). Vasopressin reduces cogen metabolized.17 Because glycogen (Cyclorana platycephala)oftheSandy water excretion by allowing water reab- is water soluble, it also releases potas- Desert of Australia, for example, stores sorption in the collecting ducts, but it also sium and water during , ac- so much water that it may double its increases sodium and reabsorption. counting for an additional 3 ml water per weight.8 These frogs were a favorite The reduction in urea excretion by vaso- gram of glycogen metabolized.18,19 The source of water for the Tiwi people dur- pressin improves urinary concentration marked diuresis after initiation of a low- ing hot summers. Some frogs live 5 years by increasingureaaccumulationintherenal diet is partially because without drinking water, which is because medulla, which aids water reabsorption. of water released during glycogen me- they utilize water stored in their bladders tabolism.19 Although glycogen metabo- and also generate water during the me- Reducing Nonrenal Water Loss lism produces metabolic water, most tabolism of fat.7,8 The giant tortoise of Water loss also occurs through the skin organisms store more fat than glycogen. the Galapagos Islands stores water in and lungs, where it helps regulate body Thus, fat is the major source of metabolic their urinary bladder. After rain, the tor- temperature when animals are exposed water for most animals. toise voids their bladder urine (which to heat. A lack of sweating can result in a Metabolic water is used by many contains urea and other waste products) marked rise in body temperature and animals to survive periods of water and drinks copiously to refill their blad- circulatory collapse (heat shock). In shortage. Marine whales obtain much der with fresh water. When needed, the contrast, excessive sweating without re- of their water from the burning of fat.20 turtle reabsorbs the water through the hydration may result in hypernatremia Although capable of ingesting seawater bladder wall, while at the same time, ex- and volume depletion. and excreting a urine more concentrated creting some of its wastes into it, and Desert rodents minimize water loss by than seawater, whales rarely use this over time, the osmolarity of the bladder hiding during the day in burrows, where method for obtaining water.20 Lungfish urine increases.9 temperatures are lower and humidity is obtain water from fat metabolism while high. Lungfish coat themselves with they estivate in the mud for 1–2 years. Reduced Urinary Water Losses slime to minimize water loss as they Desert rodents, such as the sand rat Homer Smith6 proposed that the evolu- burrow and estivate in the mud. Estivat- (Psammomys obesus), have high body tion from aquatic to terrestrial environ- ing frogs (C. platycephala) form cocoons fat, which they use to generate water ments required efficient ways to excrete from sloughed epithelial layers of skin.11 during times of need. Larger desert animals, nitrogen to help minimize loss of wa- Tree frogs decrease water loss by secret- such as the camel and oryx, also use meta- ter.10 Most aquatic animals excrete am- ing an impermeable waxy material onto bolic water, and in the oryx, this may ac- monia, the simplest nitrogen product, as their skin.11 Lemurs estivate in tree hol- count for 24% of its overall water needs.21 their means for eliminating nitrogen lows to avoid sun exposure and reduce Some obligatory water loss by the waste products (ammoniotely). In con- their metabolism and water needs. The lung occurs during fat metabolism be- trast, ammonia is not an appropriate dromedary camel conserves water by cause ofthe need to excrete carbondioxide compound for nitrogen excretion by ter- minimizing sweating because of a reduc- that may counter the gain of water pro- restrial animals, because its renal excre- tion in sweat glands. The camel also does vided during fat metabolism.22 However, tion requires 400 ml water per 1 gram not pant and has adaptations in its nose animals like camels have developed tech- ammonia and blood levels .0.05 mM that minimize respiratory losses of wa- niques to reduce water loss from their air- are neurotoxic.10 Rather, urea excretion ter.12,13 The consequence is significant ways and skin.12,13 is common among land amphibians and diurnal variation in body temperature , because it is concentrated (as much as 6°C), with temperatures oc- easily and with low toxicity. Most effec- casionally reaching 40°C on hot days.12 To SURVIVAL MECHANISMS tive is excretion of uric acid (uricotely), prevent dehydration, camels ingest large ASSOCIATED WITH which requires only 1/50 the amount of volumes (up to 57 L) of water at one sit- DEHYDRATION water as that for the excretion of ammo- ting. Despite these preventive measures, nia. Excretion of uric acid is the principal camels can become severely dehydrated.14 Because fat and glycogen act as storage mechanism for nitrogen excretion in for water, it is not surprising that survival birds, reptiles, and some amphibians.10 Metabolic Water mechanisms associated with starvation Here, the uric acid is precipitated in the Water is also generated during fat and and water shortage have overlapping cloaca, where the last water is absorbed, glycogen metabolism. Fat is anhydrous metabolic pathways. Here, we discuss and then, the urate pellet is excreted. andcontainsonly10%waterbyweight,15 some of these mechanisms.

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Vasopressin: The Survival Hormone Vasopressin also may stimulate fat stress responses is reminiscent of the ef- Vasopressin is an old hormone, with its accumulation. Vasopressin blocks fat fects of fructose.43 It is of interest that predecessor, vasotocin, appearing 700 oxidation31,32 and enhances fat accumu- fructose, but not glucose, stimulates va- million years ago.23 Although vasopres- lation by blocking lipolysis in fasting sopressin release in humans.44,45 We re- sin reduces urinary water losses in animals.32,35,36 In fasting animals, vaso- cently showed that orally administered response to a loss of intracellular or ex- pressin reduces ketosis but increases fructose augments circulating vasopres- tracellular fluid, it has other actions that glucose levels.32 Vasopressin enhances sin levels (as determined by measuring may aid water conservation.24 For exam- insulin resistance and fatty liver accu- copeptin, a validated biomarker for va- ple, vasopressin may also reduce nonre- mulation in the obese Zucker rat.37 sopressin46) and urinary concentration nal water loss25,26 by acting via V2 Vasopressin secretion is associated with in dehydrated rats.47 Fructose also stim- receptors in the lungs.27 Vasopressin stress responses that improve chances ulates urinary sodium reabsorption48 also reduces fever because of antipyretic for survival. For example, vasopressin and reduces urea excretion49 similar to effects that reduce water loss.24 In frogs, acutely increases BP and induces vascular vasopressin. vasotocin reduces water loss through the constriction via the V1a receptor.35 Va- Dehydration also results in endoge- skin and stimulates water reabsorption sopressin stimulates adrenocorticotro- nous fructose production because of ac- from the bladder when frogs are exposed phic hormone release from the anterior tivation of the aldose reductase-sorbitol to dehydrating stimuli.11,23 In humans, pituitary via the V1b receptor38,39 and dehydrogenase (polyol) pathway.50 We however, the reduction of sweating in catecholamine release from the adrenal found that acutely dehydrated mice dehydrated individuals occurs via a medulla, where both V1a and V1b recep- show a blunted vasopressin response if vasopressin-independent mechanism.28,29 tors are expressed.40 Vasopressin acti- endogenous fructose metabolism is abol- Vasopressin has other survival func- vates the renin-angiotensin system35 ished (by using fructokinase knockout tions (Figure 1). Acute infusion of vaso- and stimulates aldosterone release.35 mice) (C. Roncal-Jimenez et al.,unpub- pressin increases serum glucose in These stress responses are associated lished data). These studies emphasize humans,30 likely by stimulating glyco- with vasopressin–mediated behavioral a strong relationship between fructose genolysis and gluconeogenesis.31–34 Va- changes that include aggression, anxiety, and vasopressin. sopressin stimulates glucagon release impulsivity, and memory.36,41,42 We speculate that fructose may be a from islet cells.34 Vasopressin stimulates primary nutrient for survival, especially sodium reabsorption in the cortical and Fructose: The Survival Nutrient under conditions of reduced food or outer medullary collecting ducts.24 The effect of vasopressin to stimulate fat water availability. Indeed, the adminis- Vasopressin also stimulates protein syn- accumulation (by blocking fat oxida- tration of fructose to fasting humans thesis, cell proliferation, and cell hyper- tion), increase blood glucose (via gluco- increases glucose levels (likely from the trophy in vitro.35 neogenesis), increase BP, and stimulate metabolism of fructose itself) and reduces

Figure 1. Vasopressin, the ultimate survival hormone. Vasopressin may have originated as a survival hormone for situations where the organism suffered from either extracellular volume or intracellular volume loss. The effects of vasopressin include actions much greater than simply preventing the loss of water but also, include generating a stress response, increasing BP, stimulating protein synthesis, stimulating fat accumulation, and maintaining elevated serum glucose (insulin resistance) to provide energy to the brain. ACTH, adrenocorticotrophic hormone; CNS, central nervous system; RAS, renin angiotensin system.

J Am Soc Nephrol 27: 2247–2256, 2016 Biology of Dehydration 2249 SPECIAL ARTICLE www.jasn.org ketosis, amino acid–induced gluconeo- water losses from sweat may increase Kidney Stones genesis, urinary nitrogen (ammonia and to 3–4L/hand8Lovera24-hourpe- The risk of kidney stones is increased in urea) excretion, and sodium excretion.49 riod.15 Subjects working in hot tropical subjects with low urine output because of These are the same effects observed when environments acclimate by producing a the effect of urinary concentration to vasopressin is given to starving animals.32 higher sweat rate that is lower in so- increase concentrations of poorly soluble Thus, fructose and vasopressin may act dium, thereby resulting in less increase constituents, like calcium oxalate and similarly to preserve water, salt, and fat in core temperature, and also, they have uric acid. There is a relationship between while maintaining glucose levels as a higher plasma volume, less oxygen utili- mean daily temperature and risk for source of energy for brain function. zation, and less lactate accumulation.63 kidney stones, especially when tempera- Viewed this way, the action of vasopressin However, this adaptation may result in tures exceed 30°C.79 to stimulate fat accumulation provides a greater water loss and increased risk for mechanism for not only storing water but hyperosmolarity.63 Tohelp counter water CKD also, providing energy during times of loss from sweat, subjects living in the Heat stress doubles the risk for devel- food or water deprivation. tropics tend to have slightly higher core oping CKD among those working in temperatures during the day, with a hot environments.80 Recently, epidemics Uric Acid: The Metabolic Danger greater fall at night, showing a similar ofCKDhavebeenreportedinIndia,Sri Signal trend as that observed in camels.64 Lanka, Mexico, and Central Amer- As discussed earlier, birds and reptiles Dehydration develops easily in the hot ica.81–86 The CKD observed in these excrete uric acid as their primary means environment. An increase in serum os- areas is not because of the classic causes for excreting nitrogen to minimize water molarity of 10 mosM/kg occurs within of CKD, such as diabetes or hyperten- loss.10 Despite uric acid being a potent 40 minutes of exercise in the heat65 or sion, but rather, seems to be a type of extracellular antioxidant,51 theuricacid with water deprivation for 24 hours.66,67 chronic tubulointerstitial disease.87,88 generated during fructose metabolism The Tsimane Indians of the Amazon Although the roles of toxins and infec- stimulates hepatic fat accumulation (by show evidence of dehydration in 40% of tions have not been completely ruled blocking fat oxidation) and gluconeo- subjects, especially on days with high tem- out, common risk factors for each of genesis, increases BP, and stimulates im- peratures and strenuous physical activity, the epidemics are hot temperatures and pulsivity in laboratory animals.52–56 In despite mean water intake of 6 L daily.68 recurrent dehydration that can be linked rodents, uric acid potentiates the effect Chronic recurrent dehydration is also with climate change.89 of fructose to stimulate hepatic fat accu- common in sugar cane workers in Cen- Althoughacutedehydrationisknown mulation and gluconeogenesis.57,58 tral America who work under hot and to cause a transient reduction in kidney These data suggest that uric acid may humid conditions.69–71 After dehydra- function without permanent renal dam- also be a metabolic survival factor, which tion occurs, mental and physical perfor- age, chronic recurrent heat–induced de- is consistent with observations that se- mance worsen,65,72,73 total sweat volume hydration causes CKD in mice.50 The rum uric acid increases with both dehy- decreases,74 and relative water content of mechanism for CKD may involve hyper- dration and starvation.59 sweat decreases (reflected by higher so- osmolarity-induced alteration of fruc- Interestingly, the rise of uric acid that dium concentration).63 Energy intake tose and vasopressin metabolism (Figure occurs with protein degradation and also decreases, which results in a reduc- 2). The rise in serum osmolarity stimu- amino acid–induced gluconeogenesis is tion in obligate osmoles required for lates vasopressin and increases intrarenal reversed with fructose in fasting hu- excretion.67 Ultimately, confusion, sei- fructose generation via activation of the mans.49 Likewise, although vasopressin zures, and coma may develop. aldose reductase pathway.50 The metab- reduces uric acid excretion in healthy olism of fructose within the proximal subjects,60 in the syndrome of inappro- Diseases Favored by Water tubule results in local oxidative stress, in- priate antidiuretic hormone, serum uric Shortage and Climate Change flammation, and uric acid generation, acid is low, and urinary uric acid excre- Heat Stroke and Acute Mortality which induce local injury.90 Experimen- tion is high.61,62 Thus, whether uric acid Heat waves increase the risk for heat tal studies also document a role for vaso- has a role in water handling remains un- stroke and heat-associated mortality.75–77 pressininCKD.91 An increase in serum clear and deserves additional studies. In 2015, .1400 deaths occurred from and urinary uric acid also occurs with heat stroke in Andhra Pradesh, India.78 heat and exercise, which increases the risk In a case-control study performed in for urinary urate crystal formation.89,92 DEHYDRATION IN HUMANS Arizona, the risk for heat-associated The possibility that dehydration may death was 3.5-fold among agricultural be a risk factor for CKD should also be Dehydration in the Hot Environment workers and 2.3-fold in construction considered. Low urine output93,94 and Humans have obligate daily water losses workers, and it was disproportionately high urine osmolarity95 predict risk for from the lungs (250 ml/d) and urine higher in Native American and Hispanic the progression of CKD. Low intake of (350–500 ml/d). In hot conditions, American men.77 plain water increases the risk for CKD,

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Figure 2. Potential mechanisms involved in heat stress–associated CKD. CKD occurring in response to recurrent dehydration may involve a variety of mechanisms. Central to the loss of water is the development of hyperosmolarity, which stimulates the release of vasopressin, and the generation of fructose in the kidney from activation of the polyol (aldose reductase-sorbitol dehydrogenase) pathway.50 Vaso- pressin acts to increase glomerular hydrostatic pressure and increases the risk for progression of kidney disease.91,123,124 Endogenous fructose production is also metabolized by fructokinase in the proximal tubule, resulting in tubular injury and the release of oxidants, uric acid, and chemokines.90 Fructose may also increase vasopressin levels,125 and likewise, rehydration with sugar beverages may provide additional fructose, with an amplification of the vasopressin and uric acid levels.47 Furthermore, other factors that may be involved include low–grade muscle injury associated with excessive physical exertion leading to subclinical rhabdomyolysis,126 an increased risk for nonsteroidal anti–inflammatory drug (NSAID) use, and rarely, hypotension from volume depletion. Volume depletion may also be as- sociated with activation of the renin-angiotensin system and development of hypokalemia, which may also play a role in kidney disease.

whereasintakeofotherbeveragesdoesnot First, obese subjects have elevated these conditions independent of energy showthesameeffect.94 Likewise, high va- plasma sodium and plasma osmolar- intake or intake of sugary bever- sopressin levels (indicated by high plasma ity.99 Second, plasma hypertonicity ages.112–114 Thus, the development of copeptin levels) are associated with in- predicts the development of diabetes obesity is not simply because of greater creased risk for microalbuminuria.96,97 in subjects .70 years old.100 Third, intake of soft drinks consequent to Currently, there is a randomized trial to subjects with metabolic syndrome salt-induced thirst, which has been determine if supplementation with water and insulin resistance have elevated suggested.115 Furthermore, subjects to increase urinary output to .3L/dslows plasma copeptin levels.101–104 Fourth, givenahigh-saltdietshowreduced the progression of CKD.98 elevated levels of plasma copeptin pre- insulin sensitivity within 5 days.116 Con- dict development of diabetes96,105 and versely, hyperinsulinemia promotes dis- Obesity, Metabolic Syndrome, and obesity.96 tal tubular sodium retention.117 Hypertension Although inadequate hydration and Hyperosmolarity likely increases the As mentioned, fructose and vasopres- hot temperatures facilitate hyperosmo- risk for obesity and metabolic syndrome sin show similar effects to increase fat larity, it could also be enhanced by a by stimulating vasopressin (Figure 3). stores and conserve water (Figure 3). high intake of salt with a less than Indeed, water loading reduced fat con- This suggests that transient elevations adequate intake of water. In this regard, tent of the liver of obese Zucker rats in serum osmolarity because of either a low water intake predicts development coupled with a reduction in vasopressin relative water deficit or a high-sodium of insulin resistance,106 whereas in- levels.37 However, hyperosmolarity is diet might be associated with increased creasing water intake is associated likely acting via another pathway as risk for obesity and metabolic syn- with weight loss, at least in overweight well. We recently found that mice fed a drome. Evidence supporting hyperos- subjects.107 High salt intake is also as- high-salt diet for 5 months develop leptin molarity as a risk factor for obesity and sociated with obesity, metabolic syn- resistance, obesity, and metabolic syn- metabolic syndrome is increasing. drome, and diabetes108–112 and predicts drome (M.A. Lanaspa et al., unpublished

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Figure 3. Modern diseases engaged by water shortage and global climate change. Although the vasopressin system was developed as a survival mechanism when the host lost either intracellular or extracellular volume, in modern society, it may, instead, be associated with the development of diseases. Climate change and water shortage triggered with diets high in fructose (sugar), salt, and umami foods may lead to overactivation of this pathway. The metabolic effects of high osmolarity may include the syndrome of obesity, metabolic syndrome, and diabetes. In contrast, recurrent dehydration and highly concentrated and acidic urine may increase the risk for crystallization of uric acid and chronic kidney damage. data). The mechanism was shown to be including kidney stones, heat stroke, and Recognizing the importance of the kid- caused by hyperosmolarity-mediated CKD. Hyperosmolarity, especially in a ney in climate change–associated disease upregulation of aldose reductase in the sedentary environment, may also in- will prepare nephrologists to face an in- liver, which resulted in endogenous fruc- crease the risk for obesity and diabetes. crease in heat stress–associated kidney tose generation via the polyol pathway. We speculate that hyperosmolarity trig- diseases predicted to occur in the next Importantly, mice unable to metabolize gers factors originally designed to aid decades. fructose because of genetic deletion of survival by increasing fat stores and fructokinase were protected from devel- conserving water, such as vasopressin, oping metabolic syndrome and fatty endogenously produced fructose, and ACKNOWLEDGMENTS liver, despite ingesting equal amounts uric acid. Overactivation of these path- of salt. ways may act in synergy with Western This work was supported by Department of Hypertonicity also regulates BP and diets high in fructose-containing sugars, Defense grant PR130106 and National In- 118–120 fi the immune system. Speci cally, a salt, and purine-rich foods to accelerate stitute of Diabetes and Digestive and Kidney high-salt diet activates a transcription the obesity and diabetes epidemics (Fig- Diseases (NIDDK) of the National Institutes 43,50,91,122 factor, NF of activated T cells 5, that ure 2). Similarly, recurrent of Health (NIH) grant R01DK108408-01A1. stimulates macrophages to sequester dehydration and heat stress may also T.J. is funded by the NIH training grant via salt in the skin, thereby modulating BP. be playing a role in causing CKD NIDDK 5T32DK007446-34. 89 Salt-induced hypertonicity also activates similar pathways. This paper is considered a contribution by T helper 17 lymphocytes involved in More studies are needed to investigate the University of Colorado Climate Change 121 host defense. the effect of climate change and water and Health consortium. shortage on kidney disease and diabetes and especially, the role of vasopressin, SUMMARY fructose, and uric acid. Intervention DISCLOSURES studies to improve worksite condi- R.J.J. has several patents and patent applications In summary, climate change and low tions and hydration among agricultural related to lowering uric acid or blocking fructose water intake are increasing our risk for workers in tropical communities and metabolism in the treatment of metabolic dis- dehydration–associated kidney diseases, other at–risk groups are recommended. eases. R.J.J. and M.A.L. are members of a startup

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