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Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance

OfficialreprintfromUpToDate
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Overviewandpathophysiologyofrenaltubularacidosisandtheeffectonpotassiumbalance
Authors
MichaelEmmett,MD
EllieKelepouris,MD,FAHA

SectionEditor
RichardHSterns,MD

DeputyEditor
JohnPForman,MD,MSc

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriately
referencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jan2016.|Thistopiclastupdated:Jun30,2015.
INTRODUCTIONThelungsandthekidneysareresponsibleforthemaintenanceofacidbasebalancewithin
thebody.Alveolarventilationremovescarbondioxide,whilethekidneysreclaimfilteredbicarbonateandexcrete
hydrogenionsproducedbythemetabolismofdietaryprotein(orbicarbonatewhenthedietgeneratesmore
basethanacid).
Theterm"renaltubularacidosis"(RTA)referstoagroupofdisordersinwhich,despitearelativelywell
preservedglomerularfiltrationrate,metabolicacidosisdevelopsbecauseofdefectsintheabilityoftherenal
tubulestoperformthenormalfunctionsrequiredtomaintainacidbasebalance[1].AllformsofRTAare
characterizedbyanormalaniongap(hyperchloremic)metabolicacidosis.Thisformofmetabolicacidosis
usuallyresultsfromeitherthenetretentionofhydrogenchlorideorasaltthatismetabolizedtohydrogen
chloride(suchasammoniumchloride)orthenetlossofsodiumbicarbonateoritsequivalent[2].Themajor
causeofanormalaniongapacidosisinpatientswithoutasignificantimpairmentinrenalfunctionisdiarrhea.
(See"Approachtotheadultwithmetabolicacidosis".)
ThistopicwillreviewtheclassificationandpathophysiologyofthedifferentformsofRTAandtheimpactthese
changeshaveonpotassiumbalance.Themajorcauses,diagnosis,andtreatmentofRTAarediscussed
separately.(See"Etiologyanddiagnosisofdistal(type1)andproximal(type2)renaltubularacidosis"and
"Treatmentofdistal(type1)andproximal(type2)renaltubularacidosis"and"Causesandevaluationof
hyperkalemiainadults"and"Etiology,diagnosis,andtreatmentofhypoaldosteronism(type4RTA)".)
RENALROLEINACIDBASEBALANCEPriortodiscussingrenaltubularacidosis(RTA),itishelpfulto
brieflyreviewthekidneys'roleinthemaintenanceofacidbasebalanceandhowdisturbancesintubularfunction
canresultinmetabolicacidosis.Tomaintainacidbasebalance,thekidneysreclaimthefilteredbicarbonateand
excretethedailyacidload,whichisprimarilyderivedfromthemetabolismofsulfurcontainingaminoacids.
ReclaimingfilteredbicarbonateMostofthebicarbonatethatisfilteredbytheglomerulusreturnstothe
circulation,predominatelyasaresultofNaHexchangebytheproximaltubules(figure1).Approximately85to
90percentofthefilteredloadisreclaimedatthissite.Bycomparison,10percentisreclaimedinthedistal
nephron,primarilyviahydrogensecretionbyaprotonpump(HATPase).Undernormalconditions,thereis
virtuallynobicarbonateinthefinalurine.
Proximal(type2)RTAoriginatesfromapartialimpairmentintheabilityoftheproximaltubuletoreclaimfiltered
bicarbonate.Thisdefectleadstoanincreaseindeliveryofbicarbonatetothedistalnephron.Sincethedistal
nephronisinitiallyoverwhelmed,bicarbonateleaksintothefinalurine,leadingtofallinserumbicarbonateand
metabolicacidosis.
AcidexcretionTheexcretionofthedailyhydrogenionloadisprimarilyafunctionofthecollectingtubules.
TheaveragedailyacidloadonatypicalWesterndietisapproximately1meq/kg.Inorderforthisacidloadtobe
excretedintheurine,theremustbebuffersinthetubularlumentobindfreehydrogenions.Ifhydrogenions
werefreeandnotbufferedintheurine,thedailyexcretionof50to70meqofacidinoneliterofurinewould
resultinaurinepHoflessthan2.5andagradientbetweenthecellinteriorandthetubularlumenof100,000to
1.SuchagradientcannotbeachievedbythetubularcellsincetheminimumurinepHinhumansis4.5to5.
Theprincipalbuffersintheurineareammonia(excretedandmeasuredasammonium)andphosphate(referred
toandmeasuredastitratableacidity).Ammoniumexcretionrequirestherenalsynthesisofammoniaandthe
secretionofhydrogenionsfromthecollectingtubularcellsintothetubularlumenwheretheyaretrappedas
ammonium(NH4+).Ammonia(NH3)diffusesfreelyacrossmembranes,whileammoniumdoesnot.
Therenaltubularproductionofammoniaisstimulatedbyintracellularacidosis.Whenthesystemicacidloadis
modestlyincreased,nearnormalbalanceismaintainedbyincreasesinammoniumproductionandexcretion
(figure2).Failuretoexcretesufficientammoniumleadstothenetretentionofhydrogenionsandthe
developmentofmetabolicacidosis.
CLASSIFICATIONTherearethreemajorformsofrenaltubularacidosis(RTA):distal(type1),proximal(type
2),andhyperkalemic.HyperkalemicRTAsincludehypoaldosteronism(type4)andadisordercalledvoltage
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dependentRTA,whichissometimesconsideredasubtypeofdistalRTA.ThesemajorformsofRTAdifferin
theirpathophysiologyandclinicalmanifestations(table1):
DistalRTAiscausedbydefectsindistalhydrogenionexcretion(table2)
ProximalRTAiscausedbydefectsthatreducethecapacitytoreclaimfilteredbicarbonateintheproximal
tubule(table3)
Hypoaldosteronismiscausedbyreductionsinaldosteronesecretionorresponsiveness(table4)
VoltagedependentRTAiscausedbydefectsindistalsodiumreabsorption
Allfourformsproducemetabolicacidosis.Changesinpotassiumbalancearecommonlyseeninpatientswith
RTA.Theeffectonpotassiumsecretionandtheplasmapotassiumconcentrationvariesamongthedifferent
typesofRTA.(See'Variablechangesinpotassiumbalance'below.)
VARIABLECHANGESINPOTASSIUMBALANCEPotassiumbalanceisfrequentlyabnormalinpatients
withrenaltubularacidosis(RTA)[3,4].Somepatientsdevelophypokalemia,andsomedevelophyperkalemia.
Howthisoccurswillbedescribedbelow,butitisusefultobeginbybrieflyreviewingnormalrenalpotassium
handling[5,6].
AlmostallofthefilteredpotassiumisreabsorbedpassivelyintheproximaltubuleandloopofHenle.Most
potassiumexcretedintheurineisderivedfrompotassiumsecretionintothetubularlumenbycellsinthedistal
nephron,particularlytheconnectingtubuleandtheprincipalcellsinthecorticalcollectingtubule[7].
Distalpotassiumsecretionisprimarilyinfluencedbytwofactors,bothofwhichpromotesodiumreabsorption:
aldosteroneandthedistaldeliveryofsodiumandwater(figure3)[5,6,8].
Aldosteroneactsinpartbyincreasingthenumberofopensodiumchannelsintheluminalmembraneof
thedistaltubule,therebyincreasingsodiumreabsorption
Distaltubulereabsorptionofsodiumismorerapidthanthatofchloride,resultinginarelatively
electronegativelumenthatprovidesafavorablegradientforpassivepotassiumsecretionfromthetubular
cellintothelumenthroughpotassiumchannelsintheluminalmembrane
AlterationsinpotassiumexcretionarecommoninpatientswithRTAand,dependinguponthesiteofthedefect
andthemechanismresponsibleforthevariousformsofRTA,canresultinhypokalemiaorhyperkalemia:
HypokalemiafrequentlydevelopsinpatientswithdistalRTA,anditusuallyimproveswithalkalitherapy.
HypokalemiamayalsodevelopinpatientswithproximalRTA.However,incontrasttodistalRTA,
hypokalemiainproximalRTAmaybecausedorexacerbatedbyalkalitherapy.(See'Distal(type1)RTA'
belowand'Proximal(type2)RTA'belowand'Effectonpotassiumexcretion'below.)
Hyperkalemiaisfrequentlyseeninpatientswithhypoaldosteronism(type4RTA)andinpatientswithother
defectsindistalnephronsodiumreabsorption(voltagedependentRTA).VoltagedependentRTAis
sometimesclassifiedasavariantofdistalRTAbut,becauseofitsclinicalsimilaritytotype4RTA,itis
discussedwithhypoaldosteronismasahyperkalemicRTA.AllformsofhyperkalemicRTAaresometimes
classifiedas"type4RTA,"butwelimitthistermtoRTAassociatedwithhypoaldosteronism.
DISTAL(TYPE1)RTADistal(type1)renaltubularacidosis(RTA)ischaracterizedbyimpairedhydrogenion
secretioninthedistalnephron.Ifsufficientlysevere,thisdefectleadstoaninabilitytoexcretethedailyacidload
(50to100meqonatypicalWesterndiet),resultinginprogressivehydrogenionretentionandanormalanion
gapmetabolicacidosis.Theplasmabicarbonateconcentrationcanfallbelow10meq/Lintheabsenceof
treatmentwithexogenousalkali.(See"Etiologyanddiagnosisofdistal(type1)andproximal(type2)renal
tubularacidosis".)
DistalRTAiscommonlyassociatedwithhypokalemiaduetorenalpotassiumwasting[3,4].Occasionally,the
hypokalemiaissufficientlysevere(ie,serumpotassiumbelow2meq/L)toproducemuscleparalysisor
respiratoryarrest[9].
TheexcretionofhydrogenionsintothelumenofthedistaltubuleisaccomplishedbytypeA(alpha)intercalated
cellsintheconnectingandcollectingtubulesviaaluminalHATPasepumpand,toalesserdegree,viaaHK
ATPasepumpthatresultsinhydrogenionsecretionandpotassiumreabsorption(figure4).Bycontrast,
potassiumsecretionoccursprimarilybytheprincipalcellsintheconnectingandcollectingtubules(figure3)
[10,11].
ImpairedhydrogenionsecretioninpatientswithdistalRTAcanbecausedbyseveraldefects:
Decreasednetactivityoftheprotonpump.(See'Decreasednetactivityoftheprotonpump'below.)
Increasedhydrogenionpermeabilityoftheluminalmembrane.(See'Increasedluminalmembrane
permeability'below.)
DecreasednetactivityoftheprotonpumpDiminishedHATPaseactivity(figure4)isprobablythemost
commoncauseofdistalRTA.Thisdefectimpairstheabilitytomaximallyacidifytheurine,andinmostpatients
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withdistalRTA,theurinepHcannotbereducedbelow5.5(normalindividualscanreducetheurinepHto5or
lower).
However,occasionalpatientswiththisformofdistalRTAcanreducetheirurinepHbelow5.5.Asanexample,in
aseriesof17patientswithprovendistalRTAduetodecreasedexpressionoftheprotonpump,twopatients
wereabletoreducetheirurinepHbelow5.5(to5.24and5.38)[12].Insuchpatients,distalRTAmaystillbe
suspectedifothercausesofanormalaniongapmetabolicacidosishavebeenexcluded,suchasdiarrhea,
kidneydisease(inwhichtheserumaniongapisusuallyelevatedbutisoccasionallynormal),proximalRTA,or
hyperkalemicRTA(table5).(See"Etiologyanddiagnosisofdistal(type1)andproximal(type2)renaltubular
acidosis",sectionon'UrinepH'.)
IftheseothercausesarenotpresentanddistalRTAisstillsuspected,thesimplestapproachistorepeatthe
measurementoftheurinepHonseveraloccasionstoseewhethervaluesof5.5orhigherareseen.Ifthisdoes
notoccur,thepresenceofanacidificationdefectcanbeidentifiedwithothertechniques,suchasmeasurement
oftheurinetobloodPCO2gradient[12,13].
Itislikelythatanumberofdifferentdefectscandirectlyorindirectlydecreasethenetactivityofthedistaltubule
protonpump[14]:
ImmunocytochemicalanalysesofrenalbiopsiesobtainedfrompatientswithSjgren'ssyndromehave
showncompleteabsenceofHATPasepumpsintheintercalatedcells(figure4)[15,16].Howimmunologic
injuryleadstothischangeisnotknown.
HightitersofanautoantibodydirectedagainstcarbonicanhydraseIIhavealsobeenidentifiedinsome
patientswithSjgren'ssyndrome[17].InhibitionofcarbonicanhydraseIIwouldbeexpectedtoimpair
intracellulargenerationofhydrogenions,whichwoulddiminishthecapacityforhydrogenionsecretionby
theprotonpump(figure4).(See"RenaldiseaseinSjgren'ssyndrome".)
Mutationsinthegeneforthechloridebicarbonateexchanger(AE1orband3)havebeenidentifiedinsome
familieswithautosomaldominant(morecommon)andautosomalrecessive(lesscommon)formsofdistal
RTA[1828].Thechloridebicarbonateexchanger,locatedonthebasolateralcellmembrane,allowsthe
celltoexportintracellularbicarbonategeneratedbytheluminalsecretionofhydrogenionstheexchanger
movesbicarbonateintotheperitubularbloodinexchangeforchloride(figure4).
Mutationsinthechloridebicarbonateexchangercanimpairhydrogenionsecretionbyatleasttwo
mechanisms:malfunctionoftheexchangerpreventsbicarbonateexitfromthecell,andtheensuingrisein
cellpHimpedeshydrogeniongenerationandsecretionand/oraberranttraffickingofthenormally
basolateralexchangertotheluminalratherthanbasolateralmembranecanresultinbicarbonatesecretion
intothelumen,neutralizingthehydrogenionsthataresecretedintothelumen[2831].
TheAE1orband3proteinisalsopresentintheredcellmembrane,andsomeAE1mutationsarean
importantcauseofhereditaryspherocytosisandSoutheastAsianovalocytosis.Thesehematologic
disordersareoftenassociatedwithdistalRTA[3234].(See"Hereditaryspherocytosis:Mechanismof
hemolysisandpathogenesis".)
MutationsinthegenesencodingtheB1andA4subunitsoftheHATPasepumpcanimpairthefunctionof
theprotonpump[23].Defectsineithersubunitmayalsobeassociatedwithsensorineuraldeafness,
suggestingthattheprotonpumpisrequiredfornormalfunctionoftheinnerear[35,36].
Untreatedpatientswithaprotonpumpdefecttendtowastepotassiumandbecomehypokalemic[4].The
potassiumwastingisgeneratedbythereductionindistalhydrogenionsecretionviaseveralmechanisms:
Sodiumthatisreabsorbedinthecollectingtubulesmust,inordertomaintainelectroneutrality,be
reabsorbedwithananion,suchaschlorideorbicarbonate,orinexchangeforacation,suchaspotassium
(figure3)orhydrogen(figure4).Ifhydrogenionsecretionisimpaired,potassiumsecretiongenerally
increases.
Inaddition,metabolicacidosisinhibitsacomponentofproximaltubulesodiumreabsorption[37].This
deliversmoresodiumtothedistaltubulesiteswherealdosteroneacts.
Potassiumwastingbythesemechanismscanbelargelyreversedbyadequatealkalitherapy(eg,sodium
bicarbonateorsodiumcitrate),whichreducespotassiumsecretionbyoneorbothofthefollowingchanges:
increasedsodiumbicarbonatedeliverytothedistalnephronraisestheurinepHandallowsmorehydrogen
tobesecretedbeforealimitingpHgradientisreachedand/ortheadministeredsodiumloadexpandsthe
extracellularfluidvolume,whichreducesaldosteronesecretionandthereforecollectingtubulesodium
reabsorptionandpotassiumsecretion.Thus,hypokalemiagenerallyresolveswithadequatetreatmentof
theacidemia.
TheacidsecretingtypeAintercalatedcellsinthecorticalandoutermedullarycollectingtubuleshavetwo
differentprotonsecretingpumpsintheluminalmembrane:anHATPasepumpthatsecreteshydrogen
ions,andanHKATPasepumpthatsecreteshydrogenionsandreabsorbspotassiumions(figure4)[38].
Inmostpatientswithhypokalemiaandpotassiumdepletion,theactivityoftheHKATPasepumpis
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appropriatelyincreased.However,inhibitionof,oradefectin,thispumpwouldreducehydrogenion
secretionandincreasenetpotassiumexcretionbydecreasingpotassiumreabsorption[39].
IncreasedluminalmembranepermeabilityTheabilitytogenerateandmaintainahighlyacidicurine
requirestheluminalmembranetoberelativelyimpermeabletohydrogenionsandcarbonicacid(H2CO3).Asan
example,whentheurinepHis5,theurinehydrogenionconcentrationis250timesthehydrogenion
concentrationintheextracellularfluid(pHof7.4).Increasedluminalmembranepermeabilitypromotesthe
backleakofsecretedhydrogenionsfromtheurinebacktotheextracellularfluid.Thisreducesurineacid
excretion.Increasedluminalpermeabilitytohydrogenionsmaybeassociatedwithincreasedluminalpotassium
andmagnesiumpermeability.Whentheseionsleakfromcells,theirconcentrationinthelumenandurine
increases.
AmphotericinBtherapyisanimportantcauseofdistalRTA.Thisisduetoenhancedmembranepermeability
thatleadstobackdiffusionofsecretedhydrogenionsoutoftheurineandalsourinarypotassiumand
magnesiumwastingduetothediffusionoftheseionsoutofthetubularcells.Theclinicalpresentationisa
normalaniongapmetabolicacidosisthatisoftenaccompaniedbyhypokalemiaand,lessfrequently,
hypomagnesemia[4042].(See"AmphotericinBnephrotoxicity",sectionon'Electrolytedisorders'.)
Similartocasescausedbyprotonpumpdefects,alkalitherapyallowsmorehydrogentobesecretedwithout
reachingthelimitingpHgradient.Thiswouldbeexpectedtodecreasepotassiumlosses.However,alkali
therapywouldnotbeexpectedtoreducethecomponentofpotassium(andmagnesium)wastingrelatedto
increasedmembranepermeabilitytotheseions.
IncompletedistalRTAPatientswithincompletedistalRTAcannotnormallyacidifytheirurine,resultingina
urinepHthatispersistently5.5orhigherasinthecompleteformsofdistalRTA.However,despitethis
abnormality,normalnetacidexcretionismaintained,andtheplasmabicarbonateconcentrationremainsinthe
normalrange[5,43].Maintenanceofanormalrateofacidexcretionisachievedbyanincreaseinammonium
excretion,whichoffsetsthereductionintitratableacidexcretioninducedbythehighurinepH.
AnimportantclinicalfeatureofincompletedistalRTAispersistenthypocitraturiawhichcontributestourinaryand
renalcalcification.(See"Riskfactorsforcalciumstonesinadults",sectionon'Hypocitraturia'.)
ThepathogenesisofincompletedistalRTAisnotwellunderstood,butthelowrateofcitrateexcretionandthe
relativelyhighrateofammoniumexcretionareconsistentwithareductioninintracellularpHwithinthecellsof
theproximaltubule[44].Theproximaltubuleisthesiteatwhichammoniaisgeneratedandmostofthefiltered
citrateisreabsorbed[45].
ThedevelopmentofalowpHwithinproximaltubulecellscouldinitiatethefollowingsequence[44]:
Proximaltubuleammoniumandhydrogenionsecretionintothelumenarebothincreased.Thisissimilarto
thenormalproximaltubuleresponsetometabolicacidosiswhichismediated,atleastinpart,byalow
intracellularpH.
ThelowerpHintheproximaltubularlumenconvertssomefilteredtrivalentcitrateanionstothedivalent
form,whichismoreefficientlyreabsorbedviathesodiumcitratecotransporterintheluminalmembrane
[45].ThereductioninintracellularpHalsoincreasesthemetabolismofcellularcitrate,whichreducesthe
intracellularcitrateconcentration,achangethatfurtherenhancescitrateentryfromthetubularlumeninto
thecell[45].
MuchoftheammoniumthatissecretedintheproximaltubuleisreabsorbedintheloopofHenle.The
ammoniaisthenrecycledwithinthemedullaandsecretedintothemedullarycollectingtubulewhereit
combineswithhydrogenionsanddrivesthefollowingreactiontotheright,raisingtheurinepH:
NH3+H+NH4+
Twopossiblepathogenicmechanismshavebeenproposedtoexplainthereductioninproximaltubule
intracellularpHinincompletedistalRTA:
Asubtledistalacidificationdefectreducestheplasmabicarbonateconcentrationintothelownormalrange,
resultinginintermittent,shortlivedepisodesofovertmetabolicacidosis[46,47].Thiscausesintracellular
acidosiswithintheproximaltubulecellsthatleadstoincreasedammoniasynthesisandexcretionaswell
asreducedurinarycitrateexcretion.Earlyinthecourse,theincreaseinammoniumexcretioncanalmost
entirelycompensateforthedistalacidificationdefect,resultinginmaintenanceofanearnormalornormal
serumbicarbonateconcentration.
Theprimarydefectisanintracellularacidosisintheproximaltubulecells[44].Thiswillinitiatethesame
sequencedescribedinthefirstmechanism,beginningwithincreasedammoniasynthesisandreduced
urinarycitrateexcretion.Ifthishypothesisiscorrect,thenincompleteRTAisnotinitiallyadistalformof
RTA.
Overaperiodoftime,somepatientswithincompletedistalRTAprogresstothecompleteformofdistalRTA.
Boththetoxiceffectofhighinterstitialammoniaconcentrationsandcalciumphosphateprecipitation(duetoboth
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thehighurinepHandthelowurinecitrateconcentration)maycontributetothedistalnephroninjury.(See"Risk
factorsforcalciumstonesinadults",sectionon'Hypocitraturia'.)
PROXIMAL(TYPE2)RTAProximal(type2)renaltubularacidosis(RTA)ischaracterizedbyadecreasein
proximalbicarbonatereabsorptivecapacity,resultinginitiallyinbicarbonatewastingandafallintheserum
bicarbonateconcentration.Anumberofdiscretetransporters,pumps,andenzymesarerequiredforthe
proximaltubuletoreclaimmostofthefilteredbicarbonate(figure1).
Morethan4000milliequivalentsoffilteredHCO3arereabsorbeddaily,primarilybyproximaltubuletransport
processes.Thisoccursinthefollowingway(figure1):
Hydrogenionsandbicarbonatearegeneratedfromcarbonicacidwithintheproximaltubulecells.The
reactionisacceleratedbytheintracellularisoformofcarbonicanhydrase(carbonicanhydraseII).The
hydrogenionsaresecretedintotheproximaltubulelumenviathesodiumhydrogenionexchangerinthe
luminalmembrane.Themovementofsodiumdowntheelectrochemicalconcentrationgradientfromthe
lumen(whereitsconcentrationissimilartoplasma)intothecell(whereitsconcentrationismuchlowerand
theelectricalchargeisnegative)driveshydrogenionsintheoppositedirection(fromthecytoplasmintothe
lumen).TheNaKATPasepumpinthebasolateralmembraneofproximaltubulecellsindirectly"drives"
thisexchangebymaintainingthelowintracellularsodiumconcentration.
HydrogenionsthatentertheproximaltubulelumenreactwithfilteredHCO3togenerateH2CO3(carbonic
acid).TheH2CO3thatisformedisthenrapidlydehydratedtoH2OandCO2thisdehydrationreactionis
catalyzedbythemembraneboundluminalenzyme,carbonicanhydraseIV.
Withinproximaltubulecells,hydrogenionsandHCO3ionsaregeneratedsimultaneously.Forevery
hydrogenionsecretedfromthecellintothelumen,anintracellularHCO3ionmustalsoexitthecellacross
theperitubularmembrane.TheHCO3exitstepoccursviaasodiumbicarbonatecotransporter.Thenet
effectofthisprocessisthat,foreveryhydrogenionmoleculesecretedintothelumen,abicarbonate
moleculeenterstheperitubularcapillary.Becauseeachhydrogenionthatentersthelumencombineswith
onebicarbonateiontoformcarbonicacid,theneteffectofthisprocessisthedisappearanceofone
bicarbonateionandonesodiumionfromthelumenandtheappearanceofonebicarbonateionandone
sodiumionintheperitubularcapillary.Thisprocessofbicarbonatereclamationisequivalenttobicarbonate
reabsorption.
Abnormalitiesofoneormoreoftheseproximaltubuletransporters,pumps,orenzymescanimpairsodium
bicarbonatereabsorptionandcausethebicarbonatewastingfoundinproximalRTA(figure1).Examples
include:
Mutationsinthegenethatencodesforoneoftheluminalmembranesodiumhydrogenexchangersare
responsibleforsomeformsofautosomaldominantdisease[48].
Mutationsinthegeneforthesodiumbicarbonatecotransporterresultinautosomalrecessiveproximal
RTA,whichisoftenassociatedwithocularabnormalitiesandshortstature[48,49].
MutationsinthegeneforcarbonicanhydraseII(carbonicanhydraseIIdeficiencysyndrome)generate
proximaland/ordistalRTAplusosteopetrosis,cerebralcalcification,andoften,mentalretardation[5052].
Drugsthatinhibitcarbonicanhydrase,suchasacetazolamide,methazolamide,dorzolamide,and
topiramate,generateproximalRTA.Variabledistalacidificationabnormalitiesmayalsobepresentsince
carbonicanhydraseisexpressedintypeAintercalatedcells,whicharepresentfromthelatedistal
convolutedtubuletotheinitialportionoftheinnermedullarycollectingduct(figure4).
Regardlessofthemechanism,thedegreeofacidosisisselflimitedinproximalRTA.Theserumbicarbonate
concentrationusuallystabilizesatalevelbetween14and20meq/L,dependinguponboththeseverityofthe
proximaldefectandtheabilityofthedistalnephrontoreabsorbtheincreasedbicarbonateloadthatescapes
fromtheproximaltubule[53].ThepotentialmagnitudeofdistaltubuleHCO3reabsorptionwasillustratedina
childwithnodemonstrableproximaltubularfunctioninwhomtheserumbicarbonateconcentrationdidnotfall
below11to12meq/L[54].
Often,proximalRTAisaccompaniedbydefectivereabsorptionofotherionsandmoleculeswhicharealso
reabsorbedbytheproximaltubule.Theseincludephosphate,uricacid,glucose,andlowmolecularweight
proteinssuchasbeta2microglobulin.GeneralizedproximaltubuledysfunctioniscalledFanconisyndrome.
Fanconisyndromeininfantsisusuallyduetooneofseveralinheritedenzymaticdisorderssuchascystinosis,
tyrosinemia,orglycogenstoragedisease(table3)[55].Proximalrenaltubulardysfunctioncanalsobecaused
byanumberofdrugsincludingifosfamide,valproicacid,andtenofovir[56].Anotherimportantcauseofacquired
proximalRTAwithFanconisyndromeinadultsisamonoclonalgammopathy[57].(See"Etiologyanddiagnosis
ofdistal(type1)andproximal(type2)renaltubularacidosis",sectionon'Proximal(type2)RTA'.)
EffectonpotassiumexcretionProximalRTAisassociatedwithvariablechangesinpotassiumexcretion
thatareaffectedbyattemptstotreattheconditionwithalkali:
Intheabsenceofalkalitherapy,theplasmabicarbonateconcentrationwillfalluntilthefilteredbicarbonate
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loadisreducedtoalevelthatpermitsallofthefilteredbicarbonatetobereabsorbedintheproximaland
collectingtubules.Oncethisoccurs,theplasmabicarbonateconcentrationstabilizesatareducedlevel
(usuallybetween14and20meq/L),thecollectingtubulescanthenfunctionnormally,theurinepHcanbe
reducedto5.3orless,anddailydietaryacidloadcanbeexcretedintheformofammoniumandtitratable
acid.
Undertheseconditions,theremaybesomeurinarypotassiumwasting[4]sinceallformsofmetabolic
acidosisdiminishproximalsodiumreabsorption[58].Theensuingsodiumlossesmaybesufficientto
causesomehypovolemiaandsecondaryhyperaldosteronism.Thecombinationofhighlevelsof
aldosteroneandincreaseddistalsodiumdeliverywillpromotesodiumreabsorptionandpotassium
secretioninthecorticalcollectingtubule(figure3).However,thisisagenerallymodesteffect,andthe
plasmapotassiumconcentrationisrelativelynormal.
Whenalkaliisadministered(eg,assodiumbicarbonateorsodiumcitrate),theplasmabicarbonate
concentrationrises.Thisincreasesthefilteredbicarbonateloadtoalevelthatexceedstheabnormally
reducedreabsorptivecapacityoftheproximaltubuletoreclaimfilteredbicarbonate.Increaseddistaltubule
deliveryofsodium,bicarbonate,andwater,combinedwithhyperaldosteronismgeneratedbythemodest
hypovolemia,stimulatespotassiumsecretioninthecorticalcollectingtubule(figure3)[4,59].Thus,most
patientswithproximalRTAwhoaretreatedwithalkalirequirepotassiumsupplements.(See"Treatmentof
distal(type1)andproximal(type2)renaltubularacidosis",sectionon'Proximal(type2)RTA'.)
HYPERKALEMICRTASodiumreabsorptionbytheprincipalcellsoftheconnectingsegmentandcortical
collectingtubule(figure3)hasamajorimpactonbothpotassiumandhydrogenionsecretionatthesesites
(figure4).Theseeffectsoccurviathefollowingmechanisms:
Sodiumreabsorptionbytheprincipalcellsismorerapidthanchloridereabsorption.Thiscreatesanegative
electricalfieldwithinthelumen.
Theluminalelectronegativitypromotessecretionofpositivelychargedpotassiumionsfromtheprincipal
cells(figure3)andhydrogenionsfromtheintercalatedcellsintothetubularlumen(figure4).
Thus,anydefectorphysiologicalterationthatimpairsorreducessodiumreabsorptionintheconnecting
segmentandcorticalcollectingtubulewilltendtoproducebothmetabolicacidosisandhyperkalemia
[60,61].
Theprincipalcausesofhyperchloremic,hyperkalemicacidosisduetoimpaireddistaltubulesodium
reabsorptionincludethefollowing:
Voltagedependentrenaltubularacidosis(RTA):
Markedlyreduceddistalsodiumdeliveryasaresultofeitherreducedsodiumintakeand/orincreased
proximaltubulesodiumreabsorption
Aninheritedoracquireddefectinthesodiumtransportmechanismsintheprincipalcells
Hypoaldosteronism:
Adefectinaldosteronesynthesis,themostimportanthormonethatregulatesdistaltubulesodium
reabsorption.Diminishedaldosteronesynthesismaybeduetoanacquiredorinheriteddefectin
adrenalsynthesisortoreducedreninand/orangiotensinIIlevels.
Resistancetotheactionofaldosterone,whichcanresultfromstructuralormoleculardefectsin
principalcellsordrugsthatantagonizealdosteroneorinhibititseffectviaothermechanisms.
ThehyperkalemiathatispresentintheseformsofRTAisamajorcontributortothemetabolicacidosis.
Hyperkalemiainhibitsammoniagenesisandreducesurineammoniumexcretion.Themechanismsresponsible
forthisinhibitionarediscussedindetailelsewhere(see"Etiology,diagnosis,andtreatmentof
hypoaldosteronism(type4RTA)",sectionon'Metabolicacidosis'and"Potassiumbalanceinacidbase
disorders",sectionon'Metabolicacidosis').Inmanypatients,correctionofthehyperkalemiareducesthe
severityofthemetabolicacidosisor,iftherearenoothercontributingfactors(suchaschronickidneydisease),
completelyreversesthemetabolicacidosis[62,63].
VoltagedependentRTAVoltagedependent(alsocalled"voltagedefect")RTAscanoccurwithmarkedly
reduceddistalsodiumdeliveryorwithinheritedoracquireddefectsinsodiumreabsorptionbytheprincipalcells
[64].Sometimes,thesedisordersareclassifiedasasubtypeofdistalRTA.However,manyexpertsinclude
voltagedependentRTAandhypoaldosteronisminthecategoryof"hyperkalemicRTA"[6466].
VoltagedependentdistalRTAhasbeendescribedinthefollowingclinicalsettings:
Severehypovolemia[67].
Urinarytractobstruction[68],whichcaninjuretubulecellsandreducetheactivityofthecellularNaK
ATPasepump.Thismaydiminishsodiumreabsorption[69].However,urinaryobstructioncanalso
generateawidespectrumofacidificationdisorders:somepatientsdevelophypoaldosteronism,others
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haveresistancetoaldosterone,andsomemaydevelopotherformsofdistaltubulevoltagedefects[68].
(See"Clinicalmanifestationsanddiagnosisofurinarytractobstructionandhydronephrosis".)
Lupusnephritis,inwhichintercalatedcellHATPaseactivityusuallyappearstobeintact(figure4)[65,70].
(See"Diagnosisandclassificationofrenaldiseaseinsystemiclupuserythematosus".)
Sicklecelldisease,inwhichbothhyperkalemicdistalRTAandhypoaldosteronismcanoccur[71].(See
"Renalmanifestationsofsicklecelldisease",sectionon'Renaltubularacidosis'.)
Drugsincludingamilorideandlithiumsalts,whichproducevoltagedefectsinanumberofexperimental
modelsandmayalsohaveothereffectsonrenaltubuleacidification[60].
HypoaldosteronismAldosteronedeficiencyorresistanceproducesahyperkalemicRTAthatissometimes
called"type4RTA."ComparedwithvoltagedependentRTA,thehyperkalemiaandmetabolicacidosis
associatedwithhypoaldosteronismismilder.Theserumbicarbonateisusuallygreaterthan15meq/L[72],and
theurinepHcanusuallybereducedbelow5.5[73].
Theacidificationdefectinmostpatientswithaldosteronedeficiencyorresistanceisthoughttobeprimarilydue
toareducedrateofprotonsecretionratherthananintrinsicdefectinthetubule'scapacitytogenerateanormal
pHgradient[74,75].Thus,whenverylittleammoniaispresentintherenaltubulelumen,thepHcanbe
appropriatelyreducedbelowpH5.5(butthequantityofexcretedacidisrelativelylow).Bycontrast,when
greateramountsofammoniaarepresentinthedistaltubule,theimpairedrateofhydrogenionsecretion
producesafasterriseintheurinepHabove5.5thanisseeninnormalsubjects.Ineithercase,thereductionin
netacidexcretionresultsinmetabolicacidosis.
Patientswithhyperkalemiausuallyhavelowerurineammonialevelsandthereforeamoreacidicurine.The
defectproducedbythevariousformsofvoltagedependentdistalRTAdiscussedaboveissimilarbutgenerally
moresevere.Inthatdisorder,theurinepHoftencannotbereducedbelow5.5butcanalsovarywiththerateof
urineammoniaexcretion.
Thesedisorders,includingrareformsofaldosteroneresistancesuchaspseudohyperaldosteronismtype2,or
Gordon'ssyndrome,arepresentedelsewhereindetail.(See"Etiology,diagnosis,andtreatmentof
hypoaldosteronism(type4RTA)".)
DistinguishingvoltagedependentRTAfromhypoaldosteronismIntheabsenceofcomplicatedtesting
thatisoftennotreadilyavailable,itmaybedifficulttodistinguishamongtheformsofhyperkalemicRTA.The
plasmaaldosteronelevelcanbereadilymeasuredand,iflow,isconsistentwithhypoaldosteronism.However,a
normalorelevatedaldosteronelevelisconsistentwitheitheraldosteroneresistanceoravoltagedependent
RTA.Tocomplicatematters,severalrelateddefectscancoexist.Asanexample,bothvoltagedependentand
aldosteroneabnormalitiescanoccurtogether[64],and,insomepatients,HATPasedefectshavealsobeen
identified[76].
Fromthetherapeuticperspective,itmaynotbeimportanttodifferentiatethesedisorders,asmanywillimprove
withcorrectionofthepatient'svolumestatusandhyperkalemia.
SUMMARY
Therearethreemajorformsofrenaltubularacidosis(RTA):distal(type1),proximal(type2),and
hyperkalemic.HyperkalemicRTAsincludehypoaldosteronism(type4)andadisordercalledvoltage
dependentRTA,whichissometimesconsideredasubtypeofdistalRTA.ThesemajorformsofRTAdiffer
intheirpathophysiologyandclinicalmanifestations(table1)(see'Classification'above):
Distal(type1)RTAischaracterizedbyimpairedhydrogenionsecretioninthedistalnephronresulting
eitherfromdecreasednetactivityoftheprotonpump(see'Decreasednetactivityoftheprotonpump'
above)orfromincreasedluminalmembranehydrogenionpermeability(see'Increasedluminal
membranepermeability'above).Theplasmabicarbonateconcentrationcanfallbelow10meq/Lin
theabsenceoftreatmentwithexogenousalkali.(See'Distal(type1)RTA'above.)
ProximalRTAiscausedbyproximaltubuledefectsthatreducethecapacitytoreclaimfiltered
bicarbonate(table3).ProximalRTAisoftenassociatedwithFanconisyndrome,whichis
characterizedbydefectivereabsorptionofothersubstancesthatarenormallyreabsorbedinthe
proximaltubule,suchasphosphate,uricacid,glucose,andaminoacids.(See'Proximal(type2)RTA'
above.)
Hypoaldosteronismiscausedbyreductionsinaldosteronesecretionorresponsiveness(table4).
(See'HyperkalemicRTA'aboveand'Hypoaldosteronism'above.)
VoltagedependentRTAiscausedbydefectsindistalsodiumreabsorption.(See'HyperkalemicRTA'
aboveand'VoltagedependentRTA'above.)
PotassiumbalanceisfrequentlyabnormalinpatientswithRTA(see'Variablechangesinpotassium
balance'above):
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Hypokalemia,duetorenalpotassiumwasting,frequentlydevelopsinpatientswithdistalRTAand
usuallyimproveswithalkalitherapy.(See'Distal(type1)RTA'above.)
HypokalemiamayalsodevelopinpatientswithproximalRTA.However,incontrasttodistalRTA,
alkalitherapyusuallygeneratesorexacerbateshypokalemiainpatientswithproximalRTA.(See
'Effectonpotassiumexcretion'above.)
Hyperkalemiaoccursfrequentlyinpatientswithhypoaldosteronism(type4RTA)andinpatientswith
otherdefectsinsodiumreabsorptionintheirdistalnephron(voltagedependentRTA).(See
'HyperkalemicRTA'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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