634P. Kimmel & M. Rosenberg (Eds): Chronic Renal
Disease.DOI: 2012 Elsevier Inc. All rights reserved. 2015
http://dx.doi.org/10.1016/B978-0-12-411602-3.00052-452INTRODUCTIONHypertensionisacommonclinicalfndingin
patientswithCKDandpresentsamajortherapeu-ticchallengeinsuchpatientsforseveralreasons.The
causesandpathogenesisofhypertensioninCKDare
multipleandcomplex.Hypertensionacceleratesthe
progressionofrenaldisease,regardlessofitscause.
CKDitselfcauseshypertension,andfurtherleadsto
progressiverenaldamageandworseningrenalfunc-tionculminatinginESRD.Finally,hypertensionisalso
thesinglemostpowerfulriskfactorforcardiovascu-lardisease(CVD)1andvascularmortality.2Ofgreater
signifcanceisthatamongindividualswithprimary
hypertension,evenamildreductioninrenalfunction, defned as GFR 14
g/day) intakebluntedtheantiproteinuriceffectofACEIther-apy and
increased the risk for ESRD, independent of BP
control.14Renin-Angiotensin-Aldosterone System
ActivationTheRAASplaysacentralroleinthepathogenesis
ofhypertensionandCKD.1518Inappropriateactivation
ofintrarenalRAAS,resultinginenhancedangiotensin
II(Ang-II)generationhasalsobeensuggestedtocon-tributetoprogressionofCKD,16butthemechanisms
involvedinRAAS-inducedrenalinjuryarecomplex
andincompletelyunderstood.Inadditiontoitsvaso-constrictorproperties,locallyproducedAng-IIexerts
multiplecellularfunctionsandaffectsintracellularsig-nalingpathways,suchaspromotingcellgrowthand
proliferation,infammation,apoptosis,andfbrogen-esis,15,18 all of
which are key events in the pathogenesis
ofhypertensionandCKD.Perhapsthemostconvinc-ingevidencefortheactiveparticipationoftheRAAS
in CKD is provided by the numerous clinical
investiga-tionsdemonstratingthatblockadeoftheRAASwith ACEIs and
ARBs effectively lowers BP and reduces
pro-teinuriaandGFRdeclineindiabeticandnon-diabetic renal
disease.1925Increased Sympathetic Nervous
SystemActivityThereisabundantevidencethattheactivityof
thesympatheticnervoussystem(SNS)iselevatedin
CKD.2632IncreasedSNSactivityinCKDwasfrstsug-gestedbyearlyclinicalstudiesshowingelevatedcircu-latinglevelsofcatecholaminesandenhancedpressor
reactivitytonorepinephrine(NE)inpatientswith
CKD.2628Furthermore,acuteandchronictreatment
withtheadrenergicinhibitorclonidineproduceda marked fall in BP and
plasma NE levels in patients with mild to moderate renal failure.
In addition, direct
micro-neurographicstudieshavedemonstratedincreased muscle
sympathetic nerve activity (MSNA) in
hyperten-sivepatientstreatedwithchronicHD.29Theincreased
MSNAobservedinthesepatientswasnormalizedby
bilateralnephrectomy,suggestingthatsympathetic
activationisreversible,andappearstobemediatedby
anafferentsignalarisinginthefailingkidneys.Klein et
al.alsoshowedthatinhypertensivepatientswith
CKD,sympatheticactivity(asquantifedbyMSNA)
isinappropriatelyelevatedforthevolumestatusand
thatreductionofnephronnumberinitselfdoesnot
infuencesympatheticactivity.33Morerecently,Grassi et
al.34showedthatMSNAisalreadyincreasedeven
intheinitialclinicalstagesofchronicrenalfailureand inversely
correlated with eGFR, suggesting that
sympa-theticoveractivityparallelstheseverityofrenalfailure
andmayparticipateinCKDprogression.Furthermore,
chronicangiotensin-convertingenzymeinhibitionand
angiotensinIIreceptorblockadewereshowntoreduce
theincreasedBPandsympatheticactivityinnormo-volemic hypertensive
patients with chronic renal failure
(CRF),35indicatingthatAngII-mediatedmechanisms
contributetothepathogenesisofsympatheticnervous overactivity in
CKD.TheimportanceofSNSactivityinCKDishigh-lightedbytherecentdiscoveryofrenalase,anovel
monoamineoxidase,synthesizedbythekidney,that degrades
catecholamines and regulates cardiac function
andBP.36,37Evidenceisemergingthatplasmarenalase
concentrationisreducedinESRDpatients,suggesting
thatrenalasedefciencymaybecausallylinkedtothe
increasedcirculatingcatecholaminelevelsobservedin
thispatientpopulation.37Morestudiesareneededto determine whether
renalase has a role in the pathogen-esis of hypertension in CKD
patients.Endothelial Dysfunction and Nitric OxideDysfunction of the
endothelium, originally identifed as an impairment of arterial
vasodilation in response to specifc stimuli such as acetylcholine
or bradykinin, has
longbeenimplicatedinthepathogenesisofhyperten-sion.38Indeed,endothelialdysfunctionisconsidered
acharacteristicfeatureofhypertensionandothercar-diovascularriskfactors.39Endothelialdysfunctionis
markedbyreducedproductionofendothelial-derived
relaxingfactor(EDRF)ornitricoxide(NO)andendo-thelial-derivedhyperpolarizingfactorandenhanced
releaseofendothelium-derivedconstrictingfactors.40
Endothelialdysfunctionhasalsobeendemonstrated
inpre-dialysisanddialyzedCKDpatients.41,42Inaddi-tion,eveninpatientswithuncomplicated,untreated
essentialhypertension,endothelialdysfunctionwas shown to be
associated with a decline in renal function,
independentofarterialpressure.43Evidencehasalso
emergedthatNOproductionisdecreasedinCKDand
furthercontributestoprogressionofkidneydamage and increase in
cardiovascular events.44The mechanisms proposed for NO defciency in
CKD include limitations on substrate (L-arginine) availability,
increased circulating levels of endogenous NO synthase (NOS)
inhibitors, particularly asymmetric dimethyl
argi-nine(ADMA)andlossofrenalNOproductiondueto
renalneuronalNOS(nNOS)alphaproteinabundance/activity.44637
ANTIHYPERTENSIVE THERAPYVIII.THERAPEUTIC CONSIDERATIONSEndothelin-1
(ET-1), an endothelial cell-derived
pep-tidewithpowerfulvasoconstrictoractivity,hasalso
beenimplicatedinthepathogenesisofhypertension
andCKD.45,46RenalproductionofET-1isincreasedin CKD in humans and
experimental animals.46 In patients
withdiabeticnephropathy,plasmaET-1levelsarecor-relatedwithS[Cr]andthedegreeofalbuminuria.47
Similarly,inhypertensivepatientswithvaryingrenal
function(eGFR),plasmaET-1correlatedwitheGFR, and predicted renal
dysfunction.48Oxidative
StressOxidativestressisastateofimbalancebetweenfree radical
production and their degradation by antioxidant
systemswithincreasedaccumulationofreactiveoxy-genspecies(ROS)inthetissuesandorgans.Oxidative
stressisanimportantphenomenonthatcontributesto
hypertensionandlinkshypertensionwithCKDand
itscomplications.4951Oxidativestresshasalsobeen
increasinglylinkedtothehighincidenceofcardiovas-cular events in
patients with
CKD.52,53Markersofoxidativestress,suchasadvancedoxi-dationproteinproducts54andF2isoprostanes,55,56are
increased in CKD and inversely correlated with GFR, sug-gesting
that oxidative stress may have an important effect on the decline
in renal function or vice versa. Mechanisms
fortheincreasedoxidativestressinCKDhavebeen described in detail in
several reviews and include a com-bination of increased ROS
production and reduced activi-ties (or clearance) of several
antioxidant pathways.ANTIHYPERTENSIVE
THERAPYEvidencefromalargenumberofclinicaltrialshas
clearlydemonstratedthebeneftsofcontrollingBPin
hypertensivepatientsinthegeneralpopulation57and
inpatientswithCKD.58,59Treatmentofhypertensionin
CKDisbasedonthepremisethattheelevatedBPnot
onlyacceleratesfurtherkidneyfailureleadingtoESRD,
butalsoconfersasubstantialriskofdamagetoother
organsystems(brain,heart,andperipheralarteries)
leadingtoexcessmorbidityandmortalityduetoCVD. Treatment
recommendations are also based on the notion
thatloweringtheBPreducestheprimaryadverseout-comes:progressionofkidneydiseaseanddevelopment
of CVD. Thus, management of hypertension in CKD has
threeprimarygoals:tolowerBP,toslowprogressionof kidney disease and
to reduce the risk of CVD.Goal BP LevelThe frst therapeutic
strategy to achieve these goals is to defne the goal BP level. How
low should BP be low-ered in CKD
patients?AccumulateddatafromnumerousRCTsinpatients
withCKDhaveclearlyshownthatreductionofBP
andproteinuriaslowedtherateofprogressionof
kidneydisease.58,59However,thisbenefcialeffect
wasobservedonlyinthosepatientswithproteinuria above1
gperday.59TheMDRDstudy,whichrandom-izedCKDpatientstoameanarterialpressure(MAP)
of92 mm Hg(equivalentto125/75 mm Hg)versus 107 mm
Hg(equivalentto140/90 mm Hg)showed
thattightBPcontrolsignifcantlyslowedtheprogres-sionofkidneydiseaseinthosewithgreaterthan1
g
ofurineproteinperday.60Basedonthesedata,sev-eralguidelinesforCKDrecommendedaBPgoalof
