Apuntes

1. Chloride isthe mostabundantanioninthe extracellularfluid(ECF) compartment.Hyperchloremia
isdefinedasanincrease inthe chloride concentrationinthe plasmawater.Hyperchloremiaanda
relative excessof chloride inthe bodyhave beenlinkedto the developmentof reducedrenal
bloodflow,1,2increasedinterstitialedemaincludinginthe kidneyandgastrointestinalsystem,3
excessmorbidityandmortalityincriticallyill patients,4,5andreducedsurvivalandrecoveryin
patientswithacute kidney injury.6Like sodiumandotherchemicalsinthe ECFcompartment,
chloride concentrationisregulated.The organthatisresponsibleforthe maintenance of chloride
balance inthe bodyis the kidney.Thisarticle reviewsthe handlingof chloride bythe kidneyand
clinical situationsinwhichhyperchloremiacanoccur.
Renal handlingof chloride The level of the chlorideinthe plasmaisregulatedbythe kidney.The
kidneyfreelyfilterschloride acrossthe basementmembranesof the glomeruli.The amountof
chloride thatisexcretedintothe urine isdeterminedbythe chloride filteredbythe glomeruli and
by a seriesof transportprocessesthatoccur alongthe nephron.Undernormal circumstances,over
60% of the filteredchlorideisabsorbedalongthe proximal tubule.Inthe earlyproximal tubule,
sodiumisabsorbedwithaproportional amountof watersothat the concentrationof sodiumdoes
not change.By contrast,bicarbonate andothernon-chlorideanionsare rapidlyabsorbedwith
sodiumandremovedfromthe filtrate7(Fig.1A).Assodiumandnonchlorideanionsare absorbed
inthe earlyproximal tubulesegments(S1andS2),the chloride concentrationinthe lumenof the
proximal tubule increases.Bythe time the tubularfluidreachesthe lastsegmentof the proximal
tubule (S3),the chloride concentrationishighwithrespecttoitsplasmaconcentrationallowing
chloride tobe passivelyabsorbeddownitsconcentrationgradient(Fig.1B).The transepithelial
permeabilityforchlorideishigherthanthe permeabilityforbicarbonate sothatdespite the
peritubular-to-lumengradientforbicarbonate,the transportof chloride leavingthe lumen
exceedsthe bicarbonate enteringthe tubularfluid.Inthe earlyportionofthe proximaltubule,
chloride absorptionalsooccursviaapical chloride-anion(formate,oxalate,base)exchangersandit
exitsthe cell viabasolateral membrane transporters8(Fig.1B).Inhyperchloremicmetabolic
acidosisdue toHCl- or ammoniumchloride-loading,the chloridereabsorptioninthe proximal
tubule isreduced,inpart,because of the reductioninorganicaniontransportersthatfacilitate
sodiumchloride transport9aswell asthe reductioninlumen-to-peritubulargradientforchloride.
The thick ascendinglimbof the loopof Henle (TALH) is animportantsite forchloride
reabsorption.10Atthissite,sodium,potassiumandchloride are concurrentlytransportedviaa
sodium-potassium-2chlorideco-transporter(NKCC2) (Fig.2).Chloride entersthe TALHcell and
leavesitsbasolateral aspectdown anelectrogenicchloridechannel orviathe electroneutral
potassiumchloride co-transporter.The movementof chloride throughthe basolateral chloride
channel (CLC-NKB) contributestothe generationof atransepithelialpositive (lumen) tonegative
(basolateral) potential gradient.
The intracellularpositivepotential thatwouldbe generatedbythe movementof chloride outof
the cell iscounterbalancedbythe basolateral electrogenicNa+–K+ATPase thattransports sodium
out of the cell inexchange forpotassiumintothe cell ina3–2 ratio.ROMK potassiumchannelson
the apical TALH cell membrane contributestothe lumenpositive(intracellularnegative)potential
throughthe conductive movementof potassiumionsfromcell tolumen.The overall effectis that
chloride,sodiumandpotassiumenterthe cell viaNKCC2,and,forthe mostpart, chloride exitsthe
cell viathe basolateral ClC-NKBchloride channel,sodiumexitsthe cell viathe Na+–K+ATPase and

2. potassiumrecyclesbackintothe lumenviathe ROMK channel or exitsbasolaterallyviathe KCl
cotransporter.The tightcouplingbetweensodiumandchloride transportinthe TALHis
underscoredbyone of the varietiesof Barttersyndrome inwhichdefectsinbasolateral chloride
channelsdisruptsodiumchloride reabsorptionandmimicsthe renal defectobservedwith
abnormal NKCC2proteins.Althoughothertransportersonthe peritubularside of the TALcell such
as the KCl co-transporterwill transportchloride inasodium-independentmanner,mostof the
chloride thatisabsorbedbythe TALH iscoupledwithsodiumreabsorption.Therefore,factorsthat
increase sodiumreabsorptioninthissegmentwill alsoincreasechloridereabsorption.Inthe distal
convolutedtubule,sodiumandchloride are transportedfromthe lumenintothe cell byasodium-
chloride co-transporter(NCC)11(Fig.3).The drivingforce formovementof chloride fromlumen
intocellscomesfromthe lumento-cellsodiumgradientthatisgeneratedbythe basolateral Na+–
K+ ATPase whichpumpssodium outof the cell therebymaintaininglow intracellularsodium
concentrations.Furtherregulationof NCCandNKCCmayoccur throughWNKkinases,whichmay
serve aschloride sensors12andcan regulate these transportersbymodifyingtraffickingortheir
phosphorylationstate.13Inlaterportionsof the distal convolutedtubule,anegative lumen
potential generatedbymovementof sodiumthroughthe apical epithelial sodiumchannel (ENaC)
can alsoserve as a drivingforce forpassive chloride reabsorption.Thus, the segmentsof distal
convolutedtubuledisplaydirectcouplingof sodiumandchloride transportviathe NCCand
indirectcouplingof transportviapassive movementdownanelectrochemical gradient.The
collectingductplaysanimportantrole indeterminingthe chloridecontentof the final urine.
Chloride reabsorptioninthisportionof the nephronhelpstoconserve chloride inresponsetolow
chloride intake andcancontribute tothe hypertensiveeffectsof ahighsodiumchloride diet.Most
of sodiumthatisreabsorbedinthe collectingductoccursinprincipal cellsviaaldosterone-
regulatedapical epithelialsodiumchannels.Chloride reabsorptioninthe collectingductcan occur
viaparacellularchloride absorptionthatisdrivenbythe lumennegative transepithelial potential
generatedbylumen-to-cellsodiumflow throughENaC(Fig.4A).Inaddition,inB-type andnon-A
non-Btype intercalatedcells,chloride canbe transportedviapendrin,achloride-bicarbonate
exchanger,withchloridemovingfromlumen-to-cell while bicarbonate secretedintothe lumen
(Fig.4B).The relationshipbetweenvarioussodiumandchloride transportprocessesinthisportion
of the nephronwasillustratedinarecentpaperby Valletandcolleagues.14The authors
performedanumberof physiological maneuverstodeterminetheireffectsonENaCandpendrin
proteinlevelsinthe kidney.Long-termNaCl loadingsignificantlydecreasedpendrinproteinlevels
while there wasadecrease inthe “active”ENaC- submitandan enhanced -subunit.A dissociation
betweensodiumandchloride transportwasobserved,however,withthe inhibitionofthe sodium-
chloride co-transporterwithhydrochlorothiazide,pendrinlevelsfell butENaClevelsincreased.
NaCl restrictionincreasedpendrinexpression.15Anenhancedluminal bicarbonate concentration
that wouldbe createdbypendrin-mediatedbicarbonate secretionaffectssodiumreabsorptionby
increasingthe activityof downstreamENaC.16Sodiumchloridetransportbyintercalatedcellscan
alsobe enhancedbythe presence of athiazide-sensitive apical sodium-dependentchloride-
bicarbonate exchanger(NDCBE,Slc4A8) whichtransports1sodiumand2 bicarbonate ionsfrom
the lumenintothe cell inexchange for1 chloride ionwhichleavesthe cell.If NDCBE transportis
coupledwithpendrin-mediatedchloride-bicarbonateexchange,the twotransportersworking
togethercouldresultinnetsodiumchloridereabsorptionfromthe lumen,asthe bicarbonate
recyclesintoandout of the cell while sodiumandchloride enterthe cell17(Fig.4B).Factorswhich

3. alterthe ratio of the amountsor activitiesof these twoanionexchangersmaydetermine the net
impacton bicarbonate secretionandchloridereabsorption.Anothertransporterwhichmaybe
involvedinexcretionof excessivechloride inthe bodyisthe Slc26A9 transporterwhichmayact as
a chloride channel inthe medullaryportionsof the collectingduct.18Itmay modifythe impactof
chloride loadsbyincreasingchloride secretionunderconditionsof chlorideexcess.Knockoutof
thisgene resultsina predispositiontohypertension.Mice deficientinthisproteindevelop
hypertensionwhenexposedtoahighsodiumchloride load.18Althoughthe Slc26a9transporter
appearsto playan importantrole inhandlinglarge sodiumchloride loads,the regulationof the
native transporteractivityinresponsetovariedsodiumchloride loadsremainsunknown.
Chloride concentrationandhyperchloremiaThe serumchloride level isgenerallymeasuredasa
concentrationof chloride ina volume of serum.The biologicallyactivechlorideconcentrationis
the concentrationof free chloride inthe plasmawater.Chloride ismostfrequentlymeasuredby
usinga silver-chloride electrodeeitherinadirector dilutedserumsample.19Automatedmethods
foundinmanylaboratoriesinvolve the dilutionof the serumsample withreagentsothatthe
volume of the sample isassumedtohave a normal watercontentandestimationsare made based
uponassuminga normal dilutionfactor.Whenthe solidcomponentsof the serumare veryhigh,
as can occur withhypertriglyceridemiaandmultiplemyeloma,pseudohypochloremiacanoccur.
Pseudohyperchloremiacanalsobe seeninbromide oriodide intoxication.The interactionof
bromide oriodide withthe silver-chloride electrode generatesagreatervoltage change thandoes
chloride givingthe impressionof excessive chloride inthe blood.20,21Causesof true
hyperchloremiaHyperchloremiafromwaterlossHyperchloremiacanresultfroma numberof
mechanisms(Table 1).Waterlossinexcessof chloride losscanraise the chloride concentration.22
In dehydration,the renal responseistoconserve waterandlowerurine output.Asthere mayalso
be a componentof volume depletionwithmore severe degreesof dehydration,conservationof
chloride aswell assodiumoccursvia increasedproximal tubule reabsorptionof chloride andother
solutes,andreduceddeliveryof chloride andsodiumtomore distal nephronsegments.The
enhancedproximal tubularreabsorptionof tubularfluidanditscontentswill notnecessarily
change the chloride concentrationasthe absorptionof fluidoccursisotonically.The treatmentof
waterdeprivationisthe judiciousadministrationof electrolyte-free waterwhichwillreduce both
the sodiumandchloride concentrations.Hyperchloremiadue toexcesschlorideexposure
Hyperchloremiacanoccur whenthe bodyis exposedtofluidsthatare highin chloride.Anextreme
example of thisissaltwaterdrowning/ingestion.The suddenlarge inputof seawater(average
salinityis3.5%) overwhelmsthe abilityof the kidneytoexcretethe sodiumchloride loadand
hypernatremiaandhyperchloremiaare common.23Nevertheless,acomponentof the
hypernatremiaandhyperchloremiaassociatedwithexcessivesaltwateringestion comesfromfluid
lossesassociatedwithdiarrheaandurinarylosses.23The treatmentof patientswith
hyperchloremiafromsaltwaterdrowningwill dependuponthe patient’svolume statusaswell as
estimatesof ongoingfluidandelectrolytelossesandthe judiciousreplace of waterand
electrolytesasneeded.A lessextreme example of hyperchloremiawithanexcessive sodium
chloride loadisthe administrationof large volumesof isotonic(0.9%) sodiumchloride solution
(normal saline) frequentlyusedforvolume resuscitationof patients.Itisnoteworthythatwhena
normal individualisgivenalarge bolusof isotonicsaline,itmaytake upto 2 daysto return to the
pre-treatmentstate of sodiumandchloride balance.24Thisretentionof chloride occurswith
exposure tothe supraphysiologiclevelsof chloride innormal saline.The normal chloride

4. concentrationinthe plasmaisinthe 95–110meq/L range,while normal salinehasa chloride
concentrationof 154meq/L.The relativelyslow excretoryresponse toisotonicsalinemaybe
relatedtoeffectsof chloride loadsonrenal bloodflow andonglomerularfiltration
(tubuloglomerularfeedback).Althoughdown-regulationof chloride reabsorptive transporter
activitiesoccurwithsodiumchlorideloading,14,25,26the rapidityof the reductionof these
transportersisnot well defined.Withisotonicsalineadministration,the bicarbonate
concentrationmayalsofall as the chloride concentrationrises.Besidesdilutionof the plasma
bicarbonate withadministrationof supraphysiologicchloride-containing,base-free solutionssuch
as normal saline,otherfactorsmayplayrolesinthe fall inbicarbonate andrise inchloride levels.
Urinary bicarbonate lossesmaycontribute tothe fall inserumbicarbonate level asthere maybe a
reductioninthe reabsorptive thresholdforbicarbonate withvolume expansion.27Thislossof
bicarbonate canoccur evenwhenthe serumbicarbonate concentrationislow.27Instudiesin
humans,overthe first24h afteran infusionof isotonicsaline is given,the lossesof sodiumand
potassiumexceedthose of chloride.The reducedexcretionof chloride incomparisontosodium
and potassiumsuggestedthe urinarylossof otheranionssuchasbicarbonate andotherorganic
anionsthatmay alsocontribute to a fall inthe serumbicarbonate concentration.24Using
balancedelectrolyte solutionsthatcontainbase orbase-equivalentsandchlorideconcentrations
that are more physiologicmaynotonlypreventthe developmentof hyperchloremicacidosis,but
may avoidsome of the possible harmful effectsof associatedwithhyperchloremicsolutionssuch
as normal saline.28,29In comparisonwithbalanced,base-containingsaltsolutions,normal saline
administrationtohealthyhumansubjectsresultedinafall inrenal bloodflow andcortical
perfusion30raisingconcernsaboutthe excessive administrationof normal saline involume
resuscitationinpatients.Nevertheless,certainclinical situationsmayfavorthe use of normal
saline includinginpatientswithhypochloremicmetabolicalkalosisorthose withcerebral edema.
HyperchloremiawithmetabolicacidosisHyperchloremiaalsooccurswhenhydrochloricacid(HCl)
isaddedto the blood.HCl is rarelygivenasa directacidifyingagentbutcanbe createdfromthe
metabolismof ammoniumchlorideorcationicaminoacidssuchas lysine andarginine.31The
generationof HCl leadstoreactionof H+ withHCO3 − that resultsinCO2 productionanda netloss
of HCO3 − andrise in chloride concentration.H+ + Cl− + Na+ + HCO3 − → Na+ + Cl− + H2CO3(CO2)
Withrespirationtitratedbicarbonate islostfromthe bodyasCO2. Thusfor everymilliequivalent
of HCl added,a milliequivalentof bicarbonate isconsumedandconvertedtoCO2 so thatthe
chloride level risestothe same extentas the bicarbonate level falls.Renaltubularacidoses
(proximal type 2RTA and distal type 1 or 4 RTA) resultinhyperchloremicmetabolicacidosis.In
proximal RTA (type 2),bicarbonate reabsorptioninthe proximal tubule isimpairedresultingin
increased lossesof bicarbonateoutof thissegment.There isalsosome disruptionof chloride
reabsorptionbecause the lackofthe extractionof bicarbonate preventsthe normal rise inluminal
chloride concentration.Nevertheless,inproximalRTA,the reductioninbicarbonate transportis
greaterthan the reductioninchloride transportsothatthere isrelativelymore chloride
reabsorbedthanbicarbonate.If carbonicanhydrase inhibitionisusedasamodel forproximal RTA,
chloride reabsorptionappearstobe lessimpairedthanbicarbonate reabsorptionasisreflectedby
a relativelymodestincreaseinthe urinarychloride excretionrate whilethe ratesof excretionof
sodium,potassiumand,presumably,bicarbonate are markedlyincreased.32Inclassical distal RTA
(type 1) or type 4 RTA, the reductioninnetacid secretionpreventsthe renal generationof new
bicarbonate byimpairingammoniumand/ortitratable acidexcretion.Asaresult,the HCl

5. generatedbymetabolismresultsinafall inbicarbonate thatis notcompensatedforbythe
generationandconservationof bicarbonateandexcretionof chloride.Aslongasrenal functionis
preserved,non-chlorideacidanionsdonotaccumulate inthe systemiccirculationmaintaininga
relativelynormal aniongap.Indeed,the renal excretionof phosphate andsulfate anions
generatedfromthe metabolismof phosphorus- andsulfur-containingaminoacids31isactually
stimulatedbyacidosis.33Anothercause of hyperchloremicmetabolicacidosisoccurswith
diarrhea.Inmany segmentsof the gastrointestinal tractandassociatedexocrine organssuchas
the pancreas,bicarbonate issecretedintothe gutinexchange forchloride sothatlossof
bicarbonate,especiallyinsecretoryformsof diarrhea,canbe associatedwithbicarbonate losses
whichare associatedwithchlorideretention.34Repairof hyperchloremicformsof metabolic
acidosisinvolvesstoppingthe ongoingcause of bicarbonate lossorHCl generationwhilegivingthe
patientbicarbonate orbase equivalents(e.g.,citrate)orallowingthe patient’skidneys to
regenerate bicarbonateif renal functionisrelativelynormal.Duringthe generationof metabolic
acidosis,there are initiallynetsodiumlossesandvolume contraction.Withmore prolonged
acidosis,there maybe sodiumretentiondue tohighaldosteronelevelsandupregulationof ENaC
inthe collectingduct.35Withprovisionof bicarbonate tocorrectthe acidosis,bicarbonate is
retainedinthe proximal tubuleandnormal chloride reabsorptionisalsore-established.The
associatedvolume re-expansionwithbicarbonate maycontributetothe fall inchloride.Whenthe
kidneysrepairthe metabolicacidosis,ammoniumchloride isexcretedinthe urine while
bicarbonate thatismade inthe proximal tubule asabyproductof the glutamine metabolismis
returnedtothe blood.