3-s2.0-B9780124116023000524-main

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