metabolic and kidney diseases in the setting of climate ... · temperatures and changing climate,...

SPECIAL ARTICLE www.jasn.org

Metabolic and Kidney Diseases in the Setting of ClimateChange, Water 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 RenalMedicine, 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

ABSTRACTClimate change (global warming) is leading to an increase in heat extremes andcoupled with increasing water shortage, provides a perfect storm for a new era ofenvironmental crises and potentially, new diseases. We use a comparative physio-logic approach to show that one of the primary mechanisms by which animalsprotect themselves against water shortage is to increase fat mass as a means forproviding metabolic water. Strong evidence suggests that certain hormones(vasopressin), foods (fructose), and metabolic products (uric acid) function assurvival signals to help reduce water loss and store fat (which also provides a sourceof metabolic water). These mechanisms are intricately linked with each other andstimulated by dehydration and hyperosmolarity. Although these mechanisms wereprotective in the setting of low sugar and low salt intake in our past, today, thecombination of diets high in fructose and salty foods, increasing temperatures, anddecreasing available water places these survival signals in overdrive and may beaccelerating the obesity and diabetes epidemics. The recent discovery of multipleepidemics of CKD occurring in agricultural workers in hot and humid environmentsmay represent harbingers of the detrimental consequences of the combination ofclimate change and overactivation of survival pathways.

J Am Soc Nephrol 27: 2247–2256, 2016. doi: 10.1681/ASN.2015121314

The 21st century is bringing new chal-lenges with population expansion, a de-crease in natural resources, and climatechange. Mean temperatures increased by0.8°C since 1880, with two thirds of thechange occurring since 1975, and theyare projected to increase by 3°C to 4°Cby the end of the 21st century.1,2 Temper-ature extremes have also increased by 75%because of climate change.3 Continuedpopulation growth and to a lesser extent,climate change have also resulted in de-creasing water resources.4,5 Today, onehalf of the world population suffer

moderate water shortage (i.e., 1.0–1.7 m3

water per person per year), and 10% haveextreme water shortage (defined as,0.5 m3 per person per year), with the pri-mary areas affected being Africa, southernand eastern Asia, and the Middle East.4

Increasing water shortage coupledwith climate change increases the riskfor dehydration-associated diseases. Forexample, there is increasing evidence thatclimate change may have a role in epi-demics of CKD that are occurring amongworkers in hot environments.6 While thislatter paper focuses on the sites of these

epidemics and their relationship to localtemperatures and changing climate, spaceconstraints prevented it from being able toaddress a more central question on the bi-ology of water conservation and how it re-lates todisease.Herewe reviewhowvariousspecies protect themselves from dehydra-tion, and we identify nutrient, hormonaland metabolic pathways triggered by hy-perosmolarity that link water conservationwith survival. We also discuss how thesepathways may predict diseases that willdominate the next millennium. Impor-tantly, climate change, heat stress, andwater shortage not only will affect kidneydisease, but risk for metabolic diseases in-cluding obesity and diabetes.

HOW ANIMALS SURVIVE WATERSHORTAGE

The transitionofvertebrates fromseabasedto land was associated with many adapta-tions, but someof themost importantweremechanisms to conserve water, including

Published online ahead of print. Publication dateavailable at www.jasn.org.

Correspondence: Dr. Richard J. Johnson, Divisionof Renal Diseases and Hypertension, University ofColorado Denver, 12700 East 19th Avenue, AuroraCO 80045. Email: [email protected]

Copyright © 2016 by the American Society ofNephrology

J Am Soc Nephrol 27: 2247–2256, 2016 ISSN : 1046-6673/2708-2247 2247

http://www.jasn.org

mailto:[email protected]

ways to store water, minimize water loss,and generate water.7

Water StorageSome terrestrial animals store water intheir bladders. The water-holding frog(Cyclorana platycephala) of the SandyDesert of Australia, for example, storesso much water that it may double itsweight.8 These frogs were a favoritesource of water for the Tiwi people dur-ing hot summers. Some frogs live 5 yearswithout drinking water, which is becausethey utilize water stored in their bladdersand also generate water during the me-tabolism of fat.7,8 The giant tortoise ofthe Galapagos Islands stores water intheir urinary bladder. After rain, the tor-toise voids their bladder urine (whichcontains urea and other waste products)and drinks copiously to refill their blad-der with fresh water. When needed, theturtle reabsorbs the water through thebladder wall, while at the same time, ex-creting some of its wastes into it, andover time, the osmolarity of the bladderurine increases.9

Reduced Urinary Water LossesHomer Smith6 proposed that the evolu-tion from aquatic to terrestrial environ-ments required efficient ways to excretenitrogen to help minimize loss of wa-ter.10 Most aquatic animals excrete am-monia, the simplest nitrogen product, astheir means for eliminating nitrogenwaste products (ammoniotely). In con-trast, ammonia is not an appropriatecompound for nitrogen excretion by ter-restrial animals, because its renal excre-tion requires 400 ml water per 1 gramammonia and blood levels .0.05 mMare neurotoxic.10 Rather, urea excretionis common among land amphibians andmammals, because it is concentratedeasily and with low toxicity. Most effec-tive is excretion of uric acid (uricotely),which requires only 1/50 the amount ofwater as that for the excretion of ammo-nia. Excretion of uric acid is the principalmechanism for nitrogen excretion inbirds, reptiles, and some amphibians.10

Here, the uric acid is precipitated in thecloaca, where the last water is absorbed,and then, the urate pellet is excreted.

Although ureotelic animals have ob-ligatewater loss to help excretemetabolicwastes, urinary loss is minimized byurinary concentration, a process largelydriven by vasopressin (or vasotocin inlower vertebrates). Vasopressin reduceswater excretion by allowing water reab-sorption in the collecting ducts, but it alsoincreases sodium and urea reabsorption.The reduction in urea excretion by vaso-pressin improves urinary concentrationby increasingureaaccumulationintherenalmedulla, which aids water reabsorption.

Reducing Nonrenal Water LossWater loss also occurs through the skinand lungs, where it helps regulate bodytemperature when animals are exposedto heat. A lack of sweating can result in amarked rise in body temperature andcirculatory collapse (heat shock). Incontrast, excessive sweating without re-hydration may result in hypernatremiaand volume depletion.

Desert rodentsminimizewater loss byhiding during the day in burrows, wheretemperatures are lower and humidity ishigh. Lungfish coat themselves withslime to minimize water loss as theyburrow and estivate in the mud. Estivat-ing frogs (C. platycephala) form cocoonsfrom sloughed epithelial layers of skin.11

Tree frogs decrease water loss by secret-ing an impermeable waxy material ontotheir skin.11 Lemurs estivate in tree hol-lows to avoid sun exposure and reducetheir metabolism and water needs. Thedromedary camel conserves water byminimizing sweating because of a reduc-tion in sweat glands. The camel also doesnot pant and has adaptations in its nosethat minimize respiratory losses of wa-ter.12,13 The consequence is significantdiurnal variation in body temperature(as much as 6°C), with temperatures oc-casionally reaching 40°C on hot days.12 Toprevent dehydration, camels ingest largevolumes (up to 57 L) of water at one sit-ting. Despite these preventive measures,camels can become severely dehydrated.14

Metabolic WaterWater is also generated during fat andglycogen metabolism. Fat is anhydrousandcontains only 10%water byweight,15

but when fat is oxidized, water and car-bon dioxide are released. For every gramof fat metabolized, 1.12 ml water is gen-erated.16 Liver or muscle glycogen alsogenerates 0.6 ml water per gram of gly-cogen metabolized.17 Because glycogenis water soluble, it also releases potas-sium and water during metabolism, ac-counting for an additional 3mlwater pergram of glycogen metabolized.18,19 Themarked diuresis after initiation of a low-carbohydrate diet is partially becauseof water released during glycogen me-tabolism.19 Although glycogen metabo-lism produces metabolic water, mostorganisms store more fat than glycogen.Thus, fat is themajor source of metabolicwater for most animals.

Metabolic water is used by manyanimals to survive periods of watershortage. Marine whales obtain muchof their water from the burning of fat.20

Although capable of ingesting seawaterand excreting a urine more concentratedthan seawater, whales rarely use thismethod for obtaining water.20 Lungfishobtain water from fat metabolism whilethey estivate in the mud for 1–2 years.Desert rodents, such as the sand rat(Psammomys obesus), have high bodyfat, which they use to generate waterduring timesofneed. Largerdesert animals,such as the camel and oryx, also use meta-bolic water, and in the oryx, this may ac-count for 24% of its overall water needs.21

Some obligatory water loss by thelung occurs during fat metabolism be-cause of theneed to excrete carbondioxidethat may counter the gain of water pro-vided during fat metabolism.22 However,animals like camels have developed tech-niques to reduce water loss from their air-ways and skin.12,13

SURVIVAL MECHANISMSASSOCIATED WITHDEHYDRATION

Because fat and glycogen act as storagefor water, it is not surprising that survivalmechanisms associated with starvationand water shortage have overlappingmetabolic pathways. Here, we discusssome of these mechanisms.

2248 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 2247–2256, 2016


Vasopressin: The Survival HormoneVasopressin is an old hormone, with itspredecessor, vasotocin, appearing 700million years ago.23 Although vasopres-sin reduces urinary water losses inresponse to a loss of intracellular or ex-tracellular fluid, it has other actions thatmay aid water conservation.24 For exam-ple, vasopressin may also reduce nonre-nal water loss25,26 by acting via V2receptors in the lungs.27 Vasopressinalso reduces fever because of antipyreticeffects that reduce water loss.24 In frogs,vasotocin reduces water loss through theskin and stimulates water reabsorptionfrom the bladder when frogs are exposedto dehydrating stimuli.11,23 In humans,however, the reduction of sweating indehydrated individuals occurs via avasopressin-independent mechanism.28,29

Vasopressin has other survival func-tions (Figure 1). Acute infusion of vaso-pressin increases serum glucose inhumans,30 likely by stimulating glyco-genolysis and gluconeogenesis.31–34 Va-sopressin stimulates glucagon releasefrom islet cells.34 Vasopressin stimulatessodium reabsorption in the cortical andouter medullary collecting ducts.24

Vasopressin also stimulates protein syn-thesis, cell proliferation, and cell hyper-trophy in vitro.35

Vasopressin also may stimulate fataccumulation. Vasopressin blocks fatoxidation31,32 and enhances fat accumu-lation by blocking lipolysis in fastinganimals.32,35,36 In fasting animals, vaso-pressin reduces ketosis but increasesglucose levels.32 Vasopressin enhancesinsulin resistance and fatty liver accu-mulation in the obese Zucker rat.37

Vasopressin secretion is associated withstress responses that improve chancesfor survival. For example, vasopressinacutely increases BP and induces vascularconstriction via the V1a receptor.35 Va-sopressin stimulates adrenocorticotro-phic hormone release from the anteriorpituitary via the V1b receptor38,39 andcatecholamine release from the adrenalmedulla, where both V1a and V1b recep-tors are expressed.40 Vasopressin acti-vates the renin-angiotensin system35

and stimulates aldosterone release.35

These stress responses are associatedwith vasopressin–mediated behavioralchanges that include aggression, anxiety,impulsivity, and memory.36,41,42

Fructose: The Survival NutrientThe effect of vasopressin to stimulate fataccumulation (by blocking fat oxida-tion), increase blood glucose (via gluco-neogenesis), increase BP, and stimulate

stress responses is reminiscent of the ef-fects of fructose.43 It is of interest thatfructose, but not glucose, stimulates va-sopressin release in humans.44,45 We re-cently showed that orally administeredfructose augments circulating vasopres-sin levels (as determined by measuringcopeptin, a validated biomarker for va-sopressin46) and urinary concentrationin dehydrated rats.47 Fructose also stim-ulates urinary sodium reabsorption48

and reduces urea excretion49 similar tovasopressin.

Dehydration also results in endoge-nous fructose production because of ac-tivation of the aldose reductase-sorbitoldehydrogenase (polyol) pathway.50 Wefound that acutely dehydrated miceshow a blunted vasopressin response ifendogenous fructose metabolism is abol-ished (by using fructokinase knockoutmice) (C. Roncal-Jimenez et al., unpub-lished data). These studies emphasizea strong relationship between fructoseand vasopressin.

We speculate that fructose may be aprimary nutrient for survival, especiallyunder conditions of reduced food orwater availability. Indeed, the adminis-tration of fructose to fasting humansincreases glucose levels (likely from themetabolism of fructose itself) and reduces

Figure 1. Vasopressin, the ultimate survival hormone. Vasopressin may have originated as a survival hormone for situations where theorganismsuffered fromeitherextracellular volumeor intracellular volume loss. Theeffectsof vasopressin includeactionsmuchgreater thansimply preventing the loss of water but also, include generating a stress response, increasing BP, stimulating protein synthesis, stimulatingfat accumulation, andmaintaining elevated serumglucose (insulin resistance) to provide energy to the brain. ACTH, adrenocorticotrophichormone; CNS, central nervous system; RAS, renin angiotensin system.

J Am Soc Nephrol 27: 2247–2256, 2016 Biology of Dehydration 2249

www.jasn.org SPECIAL ARTICLE

ketosis, amino acid–induced gluconeo-genesis, urinary nitrogen (ammonia andurea) excretion, and sodium excretion.49

These are the same effects observed whenvasopressin is given to starving animals.32

Thus, fructose and vasopressin may actsimilarly to preserve water, salt, and fatwhile maintaining glucose levels as asource of energy for brain function.Viewed this way, the action of vasopressinto stimulate fat accumulation provides amechanism for not only storing water butalso, providing energy during times offood or water deprivation.

Uric Acid: The Metabolic DangerSignalAs discussed earlier, birds and reptilesexcrete uric acid as their primary meansfor excreting nitrogen to minimize waterloss.10 Despite uric acid being a potentextracellular antioxidant,51 the uric acidgenerated during fructose metabolismstimulates hepatic fat accumulation (byblocking fat oxidation) and gluconeo-genesis, increases BP, and stimulates im-pulsivity in laboratory animals.52–56 Inrodents, uric acid potentiates the effectof fructose to stimulate hepatic fat accu-mulation and gluconeogenesis.57,58

These data suggest that uric acid mayalso be ametabolic survival factor, whichis consistent with observations that se-rum uric acid increases with both dehy-dration and starvation.59

Interestingly, the rise of uric acid thatoccurs with protein degradation andamino acid–induced gluconeogenesis isreversed with fructose in fasting hu-mans.49 Likewise, although vasopressinreduces uric acid excretion in healthysubjects,60 in the syndrome of inappro-priate antidiuretic hormone, serum uricacid is low, and urinary uric acid excre-tion is high.61,62 Thus, whether uric acidhas a role in water handling remains un-clear and deserves additional studies.

DEHYDRATION IN HUMANS

Dehydration in the Hot EnvironmentHumans have obligate daily water lossesfrom the lungs (250 ml/d) and urine(350–500 ml/d). In hot conditions,

water losses from sweat may increaseto 3–4 L/h and 8 L over a 24-hour pe-riod.15 Subjects working in hot tropicalenvironments acclimate by producing ahigher sweat rate that is lower in so-dium, thereby resulting in less increasein core temperature, and also, they havehigher plasma volume, less oxygen utili-zation, and less lactate accumulation.63

However, this adaptation may result ingreater water loss and increased risk forhyperosmolarity.63 To help counter waterloss from sweat, subjects living in thetropics tend to have slightly higher coretemperatures during the day, with agreater fall at night, showing a similartrend as that observed in camels.64

Dehydrationdevelops easily in the hotenvironment. An increase in serum os-molarity of 10 mosM/kg occurs within40 minutes of exercise in the heat65 orwith water deprivation for 24 hours.66,67

The Tsimane Indians of the Amazonshow evidence of dehydration in 40% ofsubjects, especially on dayswith high tem-peratures and strenuous physical activity,despite mean water intake of 6 L daily.68

Chronic recurrent dehydration is alsocommon in sugar cane workers in Cen-tral America who work under hot andhumid conditions.69–71 After dehydra-tion occurs, mental and physical perfor-mance worsen,65,72,73 total sweat volumedecreases,74 and relative water content ofsweat decreases (reflected by higher so-dium concentration).63 Energy intakealso decreases, which results in a reduc-tion in obligate osmoles required forexcretion.67 Ultimately, confusion, sei-zures, and coma may develop.

Diseases Favored by WaterShortage and Climate ChangeHeat Stroke and Acute MortalityHeat waves increase the risk for heatstroke and heat-associated mortality.75–77

In 2015, .1400 deaths occurred fromheat stroke in Andhra Pradesh, India.78

In a case-control study performed inArizona, the risk for heat-associateddeath was 3.5-fold among agriculturalworkers and 2.3-fold in constructionworkers, and it was disproportionatelyhigher in Native American and HispanicAmerican men.77

Kidney StonesThe risk of kidney stones is increased insubjectswith lowurine output because ofthe effect of urinary concentration toincrease concentrations of poorly solubleconstituents, like calcium oxalate anduric acid. There is a relationship betweenmean daily temperature and risk forkidney stones, especially when tempera-tures exceed 30°C.79

CKDHeat stress doubles the risk for devel-oping CKD among those working inhot environments.80 Recently, epidemicsof CKD have been reported in India, SriLanka, Mexico, and Central Amer-ica.81–86 The CKD observed in theseareas is not because of the classic causesof CKD, such as diabetes or hyperten-sion, but rather, seems to be a type ofchronic tubulointerstitial disease.87,88

Although the roles of toxins and infec-tions have not been completely ruledout, common risk factors for each ofthe epidemics are hot temperatures andrecurrent dehydration that can be linkedwith climate change.89

Although acutedehydration is knownto cause a transient reduction in kidneyfunctionwithout permanent renal dam-age, chronic recurrent heat–induced de-hydration causes CKD in mice.50 Themechanism for CKD may involve hyper-osmolarity-induced alteration of fruc-tose and vasopressin metabolism (Figure2). The rise in serum osmolarity stimu-lates vasopressin and increases intrarenalfructose generation via activation of thealdose reductase pathway.50 The metab-olism of fructose within the proximaltubule results in local oxidative stress, in-flammation, and uric acid generation,which induce local injury.90 Experimen-tal studies also document a role for vaso-pressin in CKD.91 An increase in serumand urinary uric acid also occurs withheat and exercise, which increases the riskfor urinary urate crystal formation.89,92

The possibility that dehydration maybe a risk factor for CKD should also beconsidered. Low urine output93,94 andhigh urine osmolarity95 predict risk forthe progression of CKD. Low intake ofplain water increases the risk for CKD,



whereas intake of other beverages does notshow the same effect.94 Likewise, high va-sopressin levels (indicated by high plasmacopeptin levels) are associated with in-creased risk for microalbuminuria.96,97

Currently, there is a randomized trial todetermine if supplementation with waterto increase urinary output to.3 L/d slowsthe progression of CKD.98

Obesity, Metabolic Syndrome, andHypertensionAs mentioned, fructose and vasopres-sin show similar effects to increase fatstores and conserve water (Figure 3).This suggests that transient elevationsin serum osmolarity because of either arelative water deficit or a high-sodiumdiet might be associated with increasedrisk for obesity and metabolic syn-drome. Evidence supporting hyperos-molarity as a risk factor for obesity andmetabolic syndrome is increasing.

First, obese subjects have elevatedplasma sodium and plasma osmolar-ity.99 Second, plasma hypertonicitypredicts the development of diabetesin subjects .70 years old.100 Third,subjects with metabolic syndromeand insulin resistance have elevatedplasma copeptin levels.101–104 Fourth,elevated levels of plasma copeptin pre-dict development of diabetes96,105 andobesity.96

Although inadequate hydration andhot temperatures facilitate hyperosmo-larity, it could also be enhanced by ahigh intake of salt with a less thanadequate intake of water. In this regard,low water intake predicts developmentof insulin resistance,106 whereas in-creasing water intake is associatedwith weight loss, at least in overweightsubjects.107 High salt intake is also as-sociated with obesity, metabolic syn-drome, and diabetes108–112 and predicts

these conditions independent of energyintake or intake of sugary bever-ages.112–114 Thus, the development ofobesity is not simply because of greaterintake of soft drinks consequent tosalt-induced thirst, which has beensuggested.115 Furthermore, subjectsgiven a high-salt diet show reducedinsulin sensitivity within 5 days.116 Con-versely, hyperinsulinemia promotes dis-tal tubular sodium retention.117

Hyperosmolarity likely increases therisk for obesity and metabolic syndromeby stimulating vasopressin (Figure 3).Indeed, water loading reduced fat con-tent of the liver of obese Zucker ratscoupled with a reduction in vasopressinlevels.37 However, hyperosmolarity islikely acting via another pathway aswell. We recently found that mice fed ahigh-salt diet for 5months develop leptinresistance, obesity, and metabolic syn-drome (M.A. Lanaspa et al., unpublished

Figure 2. Potential mechanisms involved in heat stress–associatedCKD. CKDoccurring in response to recurrent dehydrationmay involvea 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 Endogenousfructose production is also metabolized by fructokinase in the proximal tubule, resulting in tubular injury and the release of oxidants, uricacid, and chemokines.90 Fructose may also increase vasopressin levels,125 and likewise, rehydration with sugar beverages may provideadditional fructose, with an amplification of the vasopressin and uric acid levels.47 Furthermore, other factors thatmay be involved includelow–grade muscle injury associated with excessive physical exertion leading to subclinical rhabdomyolysis,126 an increased risk fornonsteroidal 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.



data). The mechanism was shown to becaused by hyperosmolarity-mediatedupregulation of aldose reductase in theliver, which resulted in endogenous fruc-tose generation via the polyol pathway.Importantly, mice unable to metabolizefructose because of genetic deletion offructokinase were protected from devel-oping metabolic syndrome and fattyliver, despite ingesting equal amountsof salt.

Hypertonicity also regulates BP andthe immune system.118–120 Specifically, ahigh-salt diet activates a transcriptionfactor, NF of activated T cells 5, thatstimulates macrophages to sequestersalt in the skin, thereby modulating BP.Salt-induced hypertonicity also activatesT helper 17 lymphocytes involved inhost defense.121

SUMMARY

In summary, climate change and lowwater intake are increasing our risk fordehydration–associated kidney diseases,

including kidney stones, heat stroke, andCKD. Hyperosmolarity, especially in asedentary environment, may also in-crease the risk for obesity and diabetes.We speculate that hyperosmolarity trig-gers factors originally designed to aidsurvival by increasing fat stores andconserving water, such as vasopressin,endogenously produced fructose, anduric acid. Overactivation of these path-ways may act in synergy with Westerndiets high in fructose-containing sugars,salt, and purine-rich foods to acceleratethe obesity and diabetes epidemics (Fig-ure 2).43,50,91,122 Similarly, recurrentdehydration and heat stress may alsobe playing a role in causing CKD viasimilar pathways.89

More studies are needed to investigatethe effect of climate change and watershortage on kidney disease and diabetesand especially, the role of vasopressin,fructose, and uric acid. Interventionstudies to improve worksite condi-tions and hydration among agriculturalworkers in tropical communities andother at–risk groups are recommended.

Recognizing the importance of the kid-ney in climate change–associated diseasewill prepare nephrologists to face an in-crease in heat stress–associated kidneydiseases predicted to occur in the nextdecades.

ACKNOWLEDGMENTS

This work was supported by Department of

Defense grant PR130106 and National In-

stitute of Diabetes and Digestive and Kidney

Diseases (NIDDK) of the National Institutes

of Health (NIH) grant R01DK108408-01A1.

T.J. is funded by the NIH training grant

NIDDK 5T32DK007446-34.

This paper is considered a contribution by

the University of Colorado Climate Change

and Health consortium.

DISCLOSURESR.J.J. has several patents and patent applications

related to lowering uric acid or blocking fructose

metabolism in the treatment of metabolic dis-

eases. R.J.J. and M.A.L. are members of a startup

Figure 3. Modern diseases engaged by water shortage and global climate change. Although the vasopressin systemwas developed as asurvivalmechanismwhen the host lost either intracellular or extracellular volume, inmodern society, it may, instead, be associatedwith thedevelopment of diseases. Climate change andwater shortage triggeredwith diets high in fructose (sugar), salt, and umami foodsmay leadto overactivation of this pathway. Themetabolic effects of high osmolarity may include the syndrome of obesity, metabolic syndrome, anddiabetes. In contrast, recurrent dehydration andhighly concentratedandacidic urinemay increase the risk for crystallizationof uric acid andchronic kidney damage.



company, Colorado ResearchPartners LLC (Aurora,

CO), that is trying to develop inhibitors of fructose

metabolism. R.J.J. also has some shares with XORT

Therapeutics (Calgary, AB, Canada), which is a

startup company developing novel xanthine

oxidase inhibitors. R.J.J. is on the Scientific Board

of Amway as well.

REFERENCES

1. NASA: Global Temperatures. Earth Observa-tory. Available at: http://earthobservatory.nasa.gov/Features/WorldOfChange/decadaltemp.php. Accessed April 20, 2016

2. Hansen J, Ruedy R, Sato M, Lo K: Globalsurface temperature change. Rev Geophys48: RG4004, 2010

3. Fischer EM, Knutti R: Anthropogenic con-tribution to global occurrence of heavyprecipitation and high temperature ex-tremes. Nat Clim Chang 5: 560–565, 2015

4. Kummu M, Ward PJ, de Moel H, Varis O: Isphysical water scarcity a new phenomenon?Global assessment of water shortage overthe last twomillennia. Environ Res Lett 5: 1–10, 2010

5. Vörösmarty CJ, Green P, Salisbury J,Lammers RB: Global water resources: Vul-nerability from climate change and pop-ulation growth. Science 289: 284–288, 2000

6. Glaser J, Lemery J, Rajagopalan B, Diaz HF,Garcia-Trabanino R, Taduri G, Madero M,AmarasingheMD,AbrahamG,AnutrakulchaiS,Jha V, Stenvinkel P, Roncal-Jiménez C,LanaspaM, Correa-Rotter R, Sheik-HamadD,BurdmannEA,Andres-HernandoA,MilagresT,Weiss I, Kanbay M, Wesseling C, Sanchez-Lozada LG, Johnson RJ: Climate Change andthe Emergent Epidemic of Chronic KidneyDisease from Heat Stress in Rural Communi-ties: The Case for Heat Stress Nephropathy[published online ahead of print May 5, 2016].ClinJAmSocNephroldoi:10.2215/CJN13841215

7. Smith HW: From Fish to Philosopher, Bos-ton, Little, Brown and Co, 1953

8. Cartledge VA, Withers PC, Bradshaw SD:Water balance and arginine vasotocin in the co-cooning frog Cyclorana platycephala (hylidae).Physiol Biochem Zool 81: 43–53, 2008

9. Jørgensen CB: Role of urinary and cloacalbladders in chelonian water economy: His-torical and comparative perspectives. BiolRev Camb Philos Soc 73: 347–366, 1998

10. Wright PA: Nitrogen excretion: Three endproducts, many physiological roles. J ExpBiol 198: 273–281, 1995

11. Jørgensen CB: 200 years of amphibian wa-ter economy: From Robert Townson to thepresent. Biol Rev Camb Philos Soc 72: 153–237, 1997

12. Schmidt-Nielsen K, Schmidt-Nielsen B,Jarnum SA, Houpt TR: Body temperature ofthe camel and its relation towater economy.Am J Physiol 188: 103–112, 1957

13. Schmidt-Nielsen K: Countercurrent systemsin animals. Sci Am 244: 118–128, 1981

14. Warda M, Prince A, Kim HK, Khafaga N,Scholkamy T, Linhardt RJ, Jin H: Proteomicsof old world camelid (Camelus dromedarius):Better understanding the interplay betweenhomeostasis and desert environment. J AdvRes 5: 219–242, 2014

15. European FoodSafety Authority (EFSA) Panelon Dietetic Products, Nutrition, and Allergies(NDA): scientific opinion on dietary referencevalues for water. EFSA J 8(3): 1–48, 2010

16. Meerman R, Brown AJ: When somebodyloses weight, where does the fat go? BMJ349: g7257, 2014

17. Mellanby K: Metabolic water and dessica-tion. Nature 150:21, 1942

18. Olsson KE, Saltin B: Variation in total bodywater with muscle glycogen changes inman. Acta Physiol Scand 80: 11–18, 1970

19. Kreitzman SN, Coxon AY, Szaz KF: Glyco-gen storage: Illusions of easy weight loss,excessive weight regain, and distortions inestimates of body composition. Am J ClinNutr 56[Suppl]: 292S–293S, 1992

20. Ortiz RM: Osmoregulation in marine mam-mals. J Exp Biol 204: 1831–1844, 2001

21. Williams JB, Ostrowski S, Bedin E, Ismail K:Seasonal variation in energy expenditure,water flux and food consumption of Arabianoryx Oryx leucoryx. J Exp Biol 204: 2301–2311, 2001

22. Mellanby K: Human water requirements.BMJ 1: 774, 1947

23. Juul KV: The evolutionary origin of thevasopressin/V2-type receptor/aquaporinaxis and the urine-concentrating mecha-nism. Endocrine 42: 63–68, 2012

24. Bankir L: Antidiuretic action of vasopressin:Quantitative aspects and interaction be-tween V1a and V2 receptor-mediated ef-fects. Cardiovasc Res 51: 372–390, 2001

25. Pouzet B, Serradeil-Le Gal C, Bouby N,Maffrand JP, Le Fur G, Bankir L: Selectiveblockade of vasopressin V2 receptors re-veals significant V2-mediated water re-absorption in Brattleboro rats with diabetesinsipidus.Nephrol Dial Transplant 16: 725–734, 2001

26. Nicco C, Wittner M, DiStefano A, Jounier S,Bankir L, Bouby N: Chronic exposure tovasopressin upregulates ENaC and sodiumtransport in the rat renal collecting duct andlung. Hypertension 38: 1143–1149, 2001

27. Fay MJ, Du J, Yu X, North WG: Evidence forexpression of vasopressin V2 receptormRNA in human lung. Peptides 17: 477–481, 1996

28. Hew-ButlerT,HummelJ,RiderBC,Verbalis JG:Characterization of the effects of the vaso-pressin V2 receptor on sweating, fluid bal-ance, and performance during exercise.Am J Physiol Regul Integr Comp Physiol307: R366–R375, 2014

29. Hew-Butler T, Noakes TD, Soldin SJ,Verbalis JG: Acute changes in arginine

vasopressin, sweat, urine and serum so-dium concentrations in exercising humans:Does a coordinated homeostatic relation-ship exist? Br J Sports Med 44: 710–715,2010

30. SpruceBA,McCullochAJ, Burd J,OrskovH,Heaton A, Baylis PH, Alberti KG: The effectof vasopressin infusion on glucose metab-olism in man.Clin Endocrinol (Oxf) 22: 463–468, 1985

31. Hems DA, Whitton PD: Stimulation byvasopressin of glycogen breakdown andgluconeogenesis in the perfused rat liver.Biochem J 136: 705–709, 1973

32. Rofe AM, Williamson DH: Metabolic effectsof vasopressin infusion in the starved rat.Reversal of ketonaemia. Biochem J 212:231–239, 1983

33. Fujiwara Y, HiroyamaM, Sanbe A, Aoyagi T,Birumachi J, Yamauchi J, Tsujimoto G,Tanoue A: Insulin hypersensitivity in micelacking the V1b vasopressin receptor.J Physiol 584: 235–244, 2007

34. FujiwaraY,HiroyamaM,SanbeA,Yamauchi J,Tsujimoto G, Tanoue A: Mutual regulationof vasopressin- and oxytocin-induced glu-cagon secretion in V1b vasopressin re-ceptor knockout mice. J Endocrinol 192:361–369, 2007

35. Koshimizu TA, Nakamura K, Egashira N,Hiroyama M, Nonoguchi H, Tanoue A: Va-sopressin V1a and V1b receptors: Frommolecules to physiological systems. PhysiolRev 92: 1813–1864, 2012

36. Rofe AM, Williamson DH: Mechanism forthe ‘anti-lipolytic’ action of vasopressin inthe starved rat. Biochem J 212: 899–902,1983

37. Taveau C, Chollet C, Waeckel L, DespositoD, Bichet DG, Arthus MF, Magnan C,Philippe E, Paradis V, Foufelle F, Hainault I,Enhorning S, Velho G, Roussel R, Bankir L,Melander O, Bouby N: Vasopressin andhydration play a major role in the develop-ment of glucose intolerance and hepaticsteatosis in obese rats. Diabetologia 58:1081–1090, 2015

38. Sugimoto T, Saito M, Mochizuki S,Watanabe Y, Hashimoto S, Kawashima H:Molecular cloning and functional expres-sion of a cDNA encoding the human V1bvasopressin receptor. J Biol Chem 269:27088–27092, 1994

39. Baertschi AJ, Friedli M: A novel type of va-sopressin receptor on anterior pituitarycorticotrophs? Endocrinology 116: 499–502, 1985

40. Itoh S, Yamada S, Mori T, Miwa T, Tottori K,Uwahodo Y, Yamamura Y, Fukuda M,Yamamoto K, Tanoue A, Tsujimoto G: At-tenuated stress-induced catecholamine re-lease in mice lacking the vasopressin V1breceptor. Am J Physiol Endocrinol Metab291: E147–E151, 2006

41. Betley JN, Xu S, Cao ZF, Gong R, MagnusCJ, Yu Y, Sternson SM: Neurons for hunger



http://earthobservatory.nasa.gov/Features/WorldOfChange/decadaltemp.php



and thirst transmit a negative-valenceteaching signal.Nature 521: 180–185, 2015

42. Caldwell HK, Lee HJ, Macbeth AH, YoungWS 3rd: Vasopressin: Behavioral roles of an“original” neuropeptide. Prog Neurobiol84: 1–24, 2008

43. Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M,Ishimoto T, Sautin YY, Lanaspa MA:Sugar, uric acid, and the etiology of di-abetes and obesity. Diabetes 62: 3307–3315, 2013

44. Wolf JP,NguyenNU,DumoulinG,BerthelayS:Influence of hypertonic monosaccharideinfusions on the release of plasma argi-nine vasopressin in normal humans. HormMetab Res 24: 379–383, 1992

45. Zerbe RL, RobertsonGL:Osmoregulation ofthirst and vasopressin secretion in humansubjects: Effect of various solutes. Am JPhysiol 244: E607–E614, 1983

46. Roussel R, Fezeu L, Marre M, Velho G,Fumeron F, Jungers P, Lantieri O, Balkau B,Bouby N, Bankir L, Bichet DG: Comparisonbetween copeptin and vasopressin in apopulation from the community and inpeople with chronic kidney disease. J ClinEndocrinol Metab 99: 4656–4663, 2014

47. García-Arroyo FE, Cristóbal M, Arellano-Buendía AS, Osorio H, Tapia E, Soto V,Madero M, Lanaspa MA, Roncal-JimenezCA, Bankir L, JohnsonRJ, Sanchez-LozadaLG:Rehydration with soft drink-like bever-ages exacerbates dehydration and worsensdehydration-associated renal injury [pub-lished online ahead of print April 6, 2016].Am J Physiol Regul Integr Comp Physiol10.1152/ajpregu.00354.2015

48. Cabral PD, HongNJ, Hye KhanMA,Ortiz PA,Beierwaltes WH, Imig JD, Garvin JL: Fruc-tose stimulates Na/H exchange activityand sensitizes the proximal tubule to an-giotensin II. Hypertension 63: e68–e73,2014

49. Gelfand RA, Sherwin RS: Nitrogen conser-vation in starvation revisited: Protein spar-ing with intravenous fructose. Metabolism35: 37–44, 1986

50. Roncal Jimenez CA, Ishimoto T, LanaspaMA, Rivard CJ, Nakagawa T, Ejaz AA,Cicerchi C, Inaba S, Le M, Miyazaki M,Glaser J, Correa-Rotter R, González MA,Aragón A, Wesseling C, Sánchez-LozadaLG, Johnson RJ: Fructokinase activity me-diates dehydration-induced renal injury.Kidney Int 86: 294–302, 2014

51. Ames BN, Cathcart R, Schwiers E, HochsteinP: Uric acid provides an antioxidant defensein humans against oxidant- and radical-caused aging and cancer: A hypothesis.Proc Natl Acad Sci U S A 78: 6858–6862,1981

52. Lanaspa MA, Cicerchi C, Garcia G, Li N,Roncal-Jimenez CA, Rivard CJ, Hunter B,Andrés-Hernando A, Ishimoto T, Sánchez-Lozada LG, Thomas J, Hodges RS,Mant CT,

Johnson RJ: Counteracting roles of AMPdeaminase and AMP kinase in the devel-opment of fatty liver. PLoS One 7: e48801,2012

53. Lanaspa MA, Sanchez-Lozada LG, Choi YJ,Cicerchi C, Kanbay M, Roncal-Jimenez CA,Ishimoto T, Li N, Marek G, Duranay M,Schreiner G, Rodriguez-Iturbe B, NakagawaT, Kang DH, Sautin YY, Johnson RJ: Uricacid induces hepatic steatosis by genera-tion of mitochondrial oxidative stress:Potential role in fructose-dependent and-independent fatty liver. J Biol Chem 287:40732–40744, 2012

54. Cicerchi C, Li N, Kratzer J, Garcia G, Roncal-Jimenez CA, Tanabe K, Hunter B, Rivard CJ,Sautin YY, Gaucher EA, Johnson RJ,Lanaspa MA: Uric acid-dependent inhibitionof AMP kinase induces hepatic glucose pro-duction in diabetes and starvation: Evolution-ary implicationsof theuricase loss in hominids.FASEB J 28: 3339–3350, 2014

55. Mazzali M, Hughes J, Kim YG, Jefferson JA,Kang DH, Gordon KL, Lan HY, Kivlighn S,Johnson RJ: Elevated uric acid increasesblood pressure in the rat by a novel crystal-independent mechanism.Hypertension 38:1101–1106, 2001

56. Sutin AR, Cutler RG, Camandola S, Uda M,Feldman NH, Cucca F, Zonderman AB,Mattson MP, Ferrucci L, Schlessinger D,Terracciano A: Impulsivity is associated withuric acid: Evidence from humans and mice.Biol Psychiatry 75: 31–37, 2014

57. Tapia E, Cristóbal M, García-Arroyo FE,Soto V, Monroy-Sánchez F, Pacheco U,Lanaspa MA, Roncal-Jiménez CA, Cruz-Robles D, Ishimoto T, Madero M, JohnsonRJ, Sánchez-Lozada LG: Synergistic effectof uricase blockade plus physiologicalamounts of fructose-glucose on glomerularhypertension and oxidative stress in rats.AmJ Physiol Renal Physiol 304: F727–F736,2013

58. Kratzer JT, Lanaspa MA, Murphy MN,Cicerchi C, Graves CL, Tipton PA, OrtlundEA, Johnson RJ, Gaucher EA: Evolutionaryhistory and metabolic insights of ancientmammalian uricases. Proc Natl Acad Sci U SA 111: 3763–3768, 2014

59. Cray C, Stremme DW, Arheart KL: Post-prandial biochemistry changes in penguins(Spheniscus demersus) including hyperuri-cemia. J Zoo Wildl Med 41: 325–326, 2010

60. Meisel A, Diamond H: Effect of vasopressinon uric acid excretion: Evidence for distalnephron reabsorption of urate in man. ClinSci Mol Med 51: 33–40, 1976

61. Beck LH: Hypouricemia in the syndrome ofinappropriate secretion of antidiuretic hor-mone. N Engl J Med 301: 528–530, 1979

62. Decaux G, Dumont I, Waterlot Y, Hanson B:Mechanisms of hypouricemia in the syn-drome of inappropriate secretion of anti-diuretic hormone. Nephron 39: 164–168,1985

63. Saat M, Sirisinghe RG, Singh R, Tochihara Y:Effects of short-term exercise in the heat onthermoregulation, blood parameters, sweatsecretion and sweat composition of tropic-dwelling subjects. J Physiol Anthropol ApplHuman Sci 24: 541–549, 2005

64. Nguyen M, Tokura H: Observations onnormal body temperatures in Vietnameseand Japanese in Vietnam. J Physiol An-thropol Appl Human Sci 21: 59–65, 2002

65. Edwards AM, Mann ME, Marfell-Jones MJ,Rankin DM, Noakes TD, Shillington DP: In-fluence of moderate dehydration on soccerperformance: Physiological responses to 45min of outdoor match-play and the imme-diate subsequent performance of sport-specific andmental concentration tests.Br JSports Med 41: 385–391, 2007

66. Geelen G, Keil LC, Kravik SE, Wade CE,Thrasher TN, Barnes PR, Pyka G, Nesvig C,Greenleaf JE: Inhibition of plasma vaso-pressin after drinking in dehydrated hu-mans. Am J Physiol 247: R968–R971,1984

67. Shirreffs SM,MersonSJ, Fraser SM,ArcherDT:The effects of fluid restriction on hydrationstatus and subjective feelings inman.Br JNutr91: 951–958, 2004

68. Rosinger A: Heat and hydration status:Predictors of repeated measures of urinespecific gravity among Tsimane’ adults inthe Bolivian Amazon. Am J Phys Anthropol158: 696–707, 2015

69. García-Trabanino R, Jarquín E, WesselingC, Johnson RJ, González-Quiroz M, Weiss I,Glaser J, José Vindell J, Stockfelt L, RoncalC, Harra T, Barregard L: Heat stress, de-hydration, and kidney function in sugarcanecutters in El Salvador–A cross-shift study ofworkers at risk of Mesoamerican nephrop-athy. Environ Res 142: 746–755, 2015

70. Laws RL, Brooks DR, Amador JJ,Weiner DE,Kaufman JS, Ramírez-Rubio O, Riefkohl A,ScammellMK, López-PilarteD, Sánchez JM,Parikh CR, McClean MD: Changes in kidneyfunction among Nicaraguan sugarcaneworkers. Int J Occup Environ Health 21:241–250, 2015

71. Laws RL, Brooks DR, Amador JJ,Weiner DE,Kaufman JS, Ramírez-Rubio O, Riefkohl A,ScammellMK, López-PilarteD, Sánchez JM,Parikh CR, McClean MD: Biomarkers of kid-ney injury among Nicaraguan sugarcaneworkers.Am J Kidney Dis 67: 209–217, 2016

72. Cade JR, Free HJ, De Quesada AM, ShiresDL, Roby L: Changes in body fluid compo-sition and volume during vigorous exerciseby athletes. J Sports Med Phys Fitness 11:172–178, 1971

73. Lieberman HR: Hydration and cognition: Acritical review and recommendations forfuture research. J Am Coll Nutr 26[Suppl]:555S–561S, 2007

74. Bourque CW: Central mechanisms of osmo-sensation and systemic osmoregulation.NatRev Neurosci 9: 519–531, 2008



75. Goforth CW, Kazman JB: Exertional heatstroke in navy and marine personnel: A hottopic. Crit Care Nurse 35: 52–59, 2015

76. Mohanaselvan A, Bhaskar E: Mortality fromnon-exertional heat stroke still high in India.Int J Occup Environ Med 5: 222–224, 2014

77. Petitti DB, Harlan SL, Chowell-Puente G,Ruddell D: Occupation and environmentalheat-associated deaths in Maricopa county,Arizona: A case-control study. PLoS One 8:e62596, 2013

78. Dearden L: Karachi heat wave: Death tolltops 1,000 as government and electricitycompany trade blame. The Independent.2015. Available at: http://www.independent.co.uk/news/world/asia/pakistan-heatwave-death-toll-tops-1000-as-government-and-electricity-company-trade-blame-10344719.html. Accessed April 20, 2016

79. TasianGE, Pulido JE,Gasparrini A, Saigal CS,Horton BP, Landis JR, Madison R, Keren R;Urologic Diseases in America Project: Dailymean temperature and clinical kidney stonepresentation in five U.S. metropolitan areas:A time-series analysis. Environ Health Per-spect 122: 1081–1087, 2014

80. Tawatsupa B, Lim LL, Kjellstrom T,Seubsman SA, Sleigh A; Thai Cohort StudyTeam: Association between occupationalheat stress and kidney disease among37,816 workers in the Thai Cohort Study(TCS). J Epidemiol 22: 251–260, 2012

81. Abraham G, Varughese S, Thandavan T,Iyengar A, Fernando E, Naqvi SAJ, Sheriff R,Ur-Rashid H, Gopalakrishnan N, Kafle RK:Chronic kidney disease hotspots in de-veloping countries in South Asia. Clin Kid-ney J 9: 135–141, 2016

82. Siriwardhana EA, Perera PA, Sivakanesan R,Abeysekara T, Nugegoda DB, JayaweeraJA: Dehydration and malaria augment therisk of developing chronic kidney disease inSri Lanka. Indian J Nephrol 25: 146–151, 2015

83. Wanigasuriya K: Update on uncertain etiol-ogy of chronic kidney disease in Sri Lanka’snorth-central dry zone. MEDICC Rev 16:61–65, 2014

84. Consultores Ambientales Asociados: In-suficiencia Renal Cronica en Tierra Blanca Ve-racruz, 1998-2003, Mexico City, Mexico, 2007.Available at: http://www.greenpeace.org/mexico/Global/mexico/Docs/2013/resumen%20ejecut%20Tierra%20Blanca%202007.pdf. Accessed April 20, 2016

85. Correa-Rotter R, Wesseling C, Johnson RJ:CKD of unknown origin in Central America:The case for a Mesoamerican nephropathy.Am J Kidney Dis 63: 506–520, 2014

86. Wesseling C, Crowe J, Hogstedt C,Jakobsson K, Lucas R, Wegman D: Meso-american Nephropathy: Report fromthe First International Research Work-shop on MeN, 2013. Available at: http://www.regionalnephropathy.org/wp-content/uploads/2013/04/Preprint-Technical-Report.pdf. Accessed December 15, 2015

87. Nanayakkara S, Komiya T, Ratnatunga N,Senevirathna ST, Harada KH, Hitomi T,Gobe G, Muso E, Abeysekera T, Koizumi A:Tubulointerstitial damage as the majorpathological lesion in endemic chronic kid-ney disease among farmers in North CentralProvince of Sri Lanka. Environ Health PrevMed 17: 213–221, 2012

88. Wijkström J, Leiva R, Elinder CG, Leiva S,Trujillo Z, Trujillo L, Söderberg M, HultenbyK, Wernerson A: Clinical and pathologi-cal characterization of Mesoamerican ne-phropathy: A new kidney disease in CentralAmerica. Am J Kidney Dis 62: 908–918,2013

89. Roncal-Jimenez C, García-Trabanino R,Barregard L, Lanaspa MA, Wesseling C,Harra T, Aragón A, Grases F, Jarquin ER,González MA, Weiss I, Glaser J, Sánchez-Lozada LG, Johnson RJ: Heat stress ne-phropathy from exercise-induced uric acidcrystalluria: A perspective on Mesoamericannephropathy. Am J Kidney Dis 67: 20–30,2016

90. Cirillo P, Gersch MS, Mu W, Scherer PM,Kim KM, Gesualdo L, Henderson GN,Johnson RJ, Sautin YY: Ketohexokinase-dependent metabolism of fructose inducesproinflammatory mediators in proximal tu-bular cells. J Am Soc Nephrol 20: 545–553,2009

91. Bouby N, Bachmann S, Bichet D, Bankir L:Effect of water intake on the progression ofchronic renal failure in the 5/6 nephrec-tomized rat. Am J Physiol 258: F973–F979,1990

92. Knochel JP, Dotin LN, Hamburger RJ: Heatstress, exercise, and muscle injury: Effectson urate metabolism and renal function.Ann Intern Med 81: 321–328, 1974

93. Clark WF, Sontrop JM, Macnab JJ, Suri RS,Moist L, Salvadori M, Garg AX: Urine vol-ume and change in estimated GFR in acommunity-based cohort study. Clin J AmSoc Nephrol 6: 2634–2641, 2011

94. Sontrop JM, Dixon SN, Garg AX, Buendia-Jimenez I, Dohein O, Huang SH, Clark WF:Association between water intake, chronickidney disease, and cardiovascular disease:A cross-sectional analysis of NHANES data.Am J Nephrol 37: 434–442, 2013

95. Plischke M, Kohl M, Bankir L, Shayganfar S,Handisurya A, Heinze G, Haas M: Urine os-molarity and risk of dialysis initiation in achronic kidney disease cohort–a possibletitration target? PLoS One 9: e93226, 2014

96. Enhörning S, Bankir L, Bouby N, Struck J,Hedblad B, Persson M, Morgenthaler NG,Nilsson PM, Melander O: Copeptin, amarker of vasopressin, in abdominal obe-sity, diabetes and microalbuminuria: Theprospective Malmö Diet and Cancer Studycardiovascular cohort. Int J Obes 37: 598–603, 2013

97. Meijer E, Bakker SJ, Halbesma N, de JongPE, Struck J, Gansevoort RT: Copeptin, a

surrogate marker of vasopressin, is associ-ated with microalbuminuria in a large pop-ulation cohort. Kidney Int 77: 29–36, 2010

98. Clark WF, Sontrop JM, Huang SH, Gallo K,Moist L, House AA, Weir MA, Garg AX: Thechronic kidney disease Water Intake Trial(WIT): Results from the pilot randomisedcontrolled trial. BMJ Open 3: e003666,2013

99. Stookey JD, Barclay D, Arieff A, Popkin BM:The altered fluid distribution in obesity mayreflect plasma hypertonicity. Eur J Clin Nutr61: 190–199, 2007

100. Stookey JD, Pieper CF, Cohen HJ: Hyper-tonic hyperglycemia progresses to diabetesfaster than normotonic hyperglycemia. Eur JEpidemiol 19: 935–944, 2004

101. Asferg CL, Andersen UB, Linneberg A,Goetze JP, Jeppesen JL: Copeptin, a sur-rogate marker for arginine vasopressin se-cretion, is associated with higher glucoseand insulin concentrations but not higherblood pressure in obese men. Diabet Med31: 728–732, 2014

102. Saleem U, Khaleghi M, Morgenthaler NG,Bergmann A, Struck J, Mosley TH Jr., KulloIJ: Plasma carboxy-terminal provasopressin(copeptin): A novel marker of insulin re-sistance and metabolic syndrome. J ClinEndocrinol Metab 94: 2558–2564, 2009

103. Enhörning S, Struck J, Wirfält E, Hedblad B,Morgenthaler NG, Melander O: Plasmacopeptin, a unifying factor behind themetabolic syndrome. J Clin EndocrinolMetab 96: E1065–E1072, 2011

104. Tenderenda-Banasiuk E, Wasilewska A,Filonowicz R, Jakubowska U, Waszkiewicz-Stojda M: Serum copeptin levels in ado-lescents with primary hypertension. PediatrNephrol 29: 423–429, 2014

105. Enhörning S, Wang TJ, Nilsson PM,Almgren P, Hedblad B, BerglundG, Struck J,Morgenthaler NG, Bergmann A, Lindholm E,Groop L, Lyssenko V, Orho-Melander M,Newton-Cheh C, Melander O: Plasma co-peptin and the risk of diabetes mellitus.Circulation 121: 2102–2108, 2010

106. Roussel R, Fezeu L, Bouby N, Balkau B,LantieriO,Alhenc-Gelas F,MarreM, Bankir L;D.E.S.I.R. Study Group: Lowwater intake andrisk for new-onset hyperglycemia. DiabetesCare 34: 2551–2554, 2011

107. Stookey JD, Constant F, Popkin BM,Gardner CD: Drinking water is associatedwith weight loss in overweight dietingwomen independent of diet and activity.Obesity (Silver Spring) 16: 2481–2488,2008

108. Baudrand R, Campino C, Carvajal CA,Olivieri O, Guidi G, Faccini G, VöhringerPA, Cerda J, Owen G, Kalergis AM,Fardella CE: High sodium intake is as-sociated with increased glucocorticoidproduction, insulin resistance and meta-bolic syndrome. Clin Endocrinol (Oxf) 80:677–684, 2014



http://www.independent.co.uk/news/world/asia/pakistan-heatwave-death-toll-tops-1000-as-government-and-electricity-company-trade-blame-10344719.html





http://www.greenpeace.org/mexico/Global/mexico/Docs/2013/resumen%20ejecut%20Tierra%20Blanca%202007.pdf




http://www.regionalnephropathy.org/wp-content/uploads/2013/04/Preprint-Technical-Report.pdf




109. Kim YC, Koo HS, Kim S, Chin HJ: Esti-mation of daily salt intake through a24-hour urine collection in Pohang,Korea. J Korean Med Sci 29[Suppl 2]:S87–S90, 2014

110. Hoffmann IS, Cubeddu LX: Salt and themetabolic syndrome. Nutr Metab Cardio-vasc Dis 19: 123–128, 2009

111. Hulthén L, Aurell M, Klingberg S, HallenbergE, Lorentzon M, Ohlsson C: Salt intake inyoung Swedish men. Public Health Nutr13: 601–605, 2010

112. Libuda L, Kersting M, Alexy U: Consump-tion of dietary salt measured by urinary so-dium excretion and its association withbody weight status in healthy children andadolescents. Public Health Nutr 15: 433–441, 2012

113. Larsen SC, Ängquist L, Sørensen TI,Heitmann BL: 24h Urinary sodium excretionand subsequent change in weight, waistcircumference and body composition. PLoSOne 8: e69689, 2013

114. HuG, Jousilahti P, PeltonenM, Lindström J,Tuomilehto J: Urinary sodium and potassiumexcretion and the risk of type 2 diabetes: Aprospective study in Finland. Diabetologia48: 1477–1483, 2005

115. He FJ, Marrero NM, MacGregor GA: Saltintake is related to soft drink consump-tion in children and adolescents: A linkto obesity? Hypertension 51: 629–634,2008

116. Donovan DS, Solomon CG, Seely EW,Williams GH, Simonson DC: Effect of so-dium intake on insulin sensitivity. Am JPhysiol 264: E730–E734, 1993

117. Stenvinkel P, Bolinder J, Alvestrand A: Ef-fects of insulin on renal haemodynamicsand the proximal and distal tubular sodiumhandling in healthy subjects. Diabetologia35: 1042–1048, 1992

118. Machnik A, Neuhofer W, Jantsch J,Dahlmann A, Tammela T, Machura K, ParkJK, Beck FX, Müller DN, Derer W, Goss J,Ziomber A, Dietsch P, Wagner H, vanRooijen N, Kurtz A, Hilgers KF, Alitalo K,Eckardt KU, Luft FC, Kerjaschki D, Titze J:Macrophages regulate salt-dependentvolume and blood pressure by a vascularendothelial growth factor-C-dependentbuffering mechanism. Nat Med 15: 545–552, 2009

119. Binger KJ, Gebhardt M, Heinig M, RintischC, Schroeder A, Neuhofer W, Hilgers K,Manzel A, Schwartz C, Kleinewietfeld M,Voelkl J, Schatz V, Linker RA, Lang F,Voehringer D, Wright MD, Hubner N,Dechend R, Jantsch J, Titze J, Müller DN:High salt reduces the activation of IL-4- andIL-13-stimulated macrophages. J Clin In-vest 125: 4223–4238, 2015

120. Titze J, Machnik A: Sodium sensing in theinterstitium and relationship to hyperten-sion. Curr Opin Nephrol Hypertens 19:385–392, 2010

121. KleinewietfeldM,ManzelA, Titze J, KvakanH,Yosef N, Linker RA, Muller DN, Hafler DA:Sodium chloride drives autoimmune diseaseby the induction of pathogenic TH17 cells.Nature 496: 518–522, 2013

122. Johnson RJ, Nakagawa T, Sánchez-LozadaLG, Lanaspa MA, Tamura Y, Tanabe K,Ishimoto T, Thomas J, Inaba S, KitagawaW,Rivard CJ: Umami: The taste that drivespurine intake. J Rheumatol 40: 1794–1796,2013

123. Bardoux P,Martin H, AhloulayM, Schmitt F,Bouby N, Trinh-Trang-Tan MM, Bankir L:Vasopressin contributes to hyperfiltration,albuminuria, and renal hypertrophy in di-abetes mellitus: Study in vasopressin-deficient Brattleboro rats. Proc Natl AcadSci U S A 96: 10397–10402, 1999

124. BoubyN,AhloulayM,NsegbeE,DéchauxM,Schmitt F, Bankir L: Vasopressin increasesglomerular filtration rate in conscious ratsthrough its antidiuretic action. J Am SocNephrol 7: 842–851, 1996

125. Wolfe BM, Ahuja SP: Effects of in-travenously administered fructose and glu-cose on splanchnic secretion of plasmatriglycerides in hypertriglyceridemic men.Metabolism 26: 963–978, 1977

126. Paula Santos U, Zanetta DM, Terra-FilhoM, Burdmann EA: Burnt sugarcane har-vesting is associated with acute renaldysfunction. Kidney Int 87: 792–799,2015



metabolic and kidney diseases in the setting of climate ... · temperatures and changing climate,...

Documents