ManagementofChronicKidneyDisease

CharlieTomson,DM,FRCPPippaBailey,MRCP,DTM&H

Managementofchronickidneydisease(CKD)requiresasystematicapproachthatincludesall components of the chronic disease model. Some causes of CKD require specific additional managementdirectedattheunderlyingcause. PrinciplesofChronicDiseaseManagement Chronic kidney disease (CKD) is a prime example of a chronic disease requiring lifelong management, involving the patient, the primary care team and specialists. Most people with CKD also have other longterm conditions (hypertension, cardiovascular disease, diabetes mellitus, atherosclerosis). Current diseasebased clinical services (eg, nephrology clinics, hypertension clinics, diabetes clinics, heart failure clinics) seldom provide optimal care, with poor communication occurring between these silos of care, and between hospitalbased clinics,theprimarycareteam,andthepatient. Thislackofintegrationisharmfulandcancontributetopatientslossofcontrolandtoconflicting messages on what drug treatment the patient should be taking. The system is also wasteful, withmuchduplicationofeffort,tests,andwastedtraveltime.Researchonsystematicattempts toachieveimprovementinthedeliveryofcareforpatientswithchronicdiseaseshasresultedin development of a framework, the chronic care model. Improvement is more likely if each component of the organization of care (selfmanagement decision support delivery system design clinical information systems) is addressed, and unlikely if, for instance, improvement 1,2 effortsareconfinedtoahospitalbasedclinic. Manyofthecomponentsofthemodel,including 3 nationalguidelinesonidentification,managementandreferral,arealreadyinplaceforCKD. 1

EarlyCKDislargelyasymptomatic,soabalancehastobestruckbetweenlabellingpatientsas having chronic kidney disease and ensuring that patients who are at increased risk of cardiovascular disease or progressive loss of kidney function are identified and offered the optionsoftreatmentthatwillreducetheserisks. DiagnosisofCKD
3,4 Inthisarticle,CKDwillbedefinedaccordingtothefivestageclassificationadoptedintheUK. This classification endorses the useof thefourvariable Modification of Diet in Renal Disease (MDRD)equationtoestimatenormalizedglomerularfiltrationrate(GFR)fromserumcreatinine, age, gender, and racial origin. The estimate provided by the laboratory should be used wherever possible, as this should include correction factors for the type of creatinine assay 4,5 used.

Somepatientswillhaveotherevidenceofchronickidneydamage,suchas:

persistentmicroalbuminuria persistentproteinuria persistenthaematuria(afterexclusionofothercauses,eg,urologicaldisease) structural abnormalities of the kidneys demonstrated on ultrasound scanning or other radiologicaltests(eg,polycystickidneydisease,refluxnephropathy)or biopsyproven chronic glomerulonephritis (most of these patients will have microalbuminuriaorproteinuria,and/orhaematuria).

6 InFebruary2007,aconsensusconferenceintheUK approvedtwoenhancementstothisfive stage classification dividing stage 3 CKD into stage 3A (estimated GFR [eGFR] 4559) and stage 3B (eGFR 3044), and adding the suffix p to the GFRbased stage for patients with proteinuria(randomurineproteintocreatinineratio>100mg/mmol).

These changes are endorsed by the National Institute for Health and Clinical Excellence 4 7 (NICE), the Scottish Intercollegiate Guidelines Network (SIGN) and the American National Kidney Frameworks National Kidney Foundation Kidney Disease Outcome Quality Initiative 8 (KDOQI) guidelines. Proteinuria should be assessed by measurement of either the urinary 9 protein to creatinine or albumin to creatinine ratio. Adoption of this enhanced classification systemislikelytofocusgreaterattentiononthosepatientsinstage3CKD,whoareatgreatest riskofcomplicationsofCKDandprogressivelossofkidneyfunction.

LimitationsofMDRDandtheCKDEPIFormula TherearemanylimitationstotheuseoftheMDRDformulatoestimaterenalfunction.First,the 2 formulaislessaccuratewhentheGFRismorethan60mL/minute/1.73m .Second,itsusehas not beenfully validated in the elderly, children or pregnant women,acute kidney injury (AKI), extremesofbodysize,orinethnicgroupsotherthanCaucasiansandAfricanAmericans.There isthereforeongoingworktofindamoreaccurateestimationofrenalfunctionthanthatoffered bytheMDRDasaresult,theCKDEPI(ChronicKidneyDiseaseEpidemiologyCollaboration) formulawaspublishedinMay2009. Preliminary work suggests that the CKDEPI equation performs better (with less bias and greater accuracy) than the MDRD formula, especially at higher GFRs, but it has not been extensively validated in the elderly or in ethnic minorities. The formula is more complex to computethantheMDRDformula,andhasnotyetbeenadoptedbyUKlaboratoriesforroutine reportingofeGFR. SpecificCausesofCKD Some cases of CKD are attributable to specific diseases, for which specific treatments are sometimesavailabletoreducetheriskofprogressivekidneydamage.However,mostpatients with these welldefined causes of CKD will also benefit from the nonspecific interventions discussedbelow. NonspecificCausesofCKD

Many patients with reduced GFR do not have proteinuria, radiological abnormalities or other markers that suggest a specific underlying cause in particular, elderly patients with reduced GFRcommonlyhavenoproteinuria.10 There is controversy about the assessment of renal function in the elderly and how renal 11 functionchangesaspartofnormalageing. TheMDRDformulaisnotaswellvalidatedinthe elderly,andanycreatininebasedformulathatincorporatesassumptionsaboutmusclemassat differentageswillfacethesameproblems.TheapparenthighprevalenceofCKDintheelderly mayoccurbecauseof:

thepresenceofnumerousriskfactorsforCKD,suchasdiabetesandhypertension an ageassociated decline in kidneyfunction that is not explained byother known risk factorsor inaccuracyofcreatininebasedestimatingequationsintheelderlypopulation.

TheBaltimoreLongitudinalStudyofAging(BLSA) suggestedthaton average kidneyfunction tends to decline with age even without comorbidities, but this decline did not appear to be 12 inevitable. The majority of CKD in theelderly is nonprogressive,and research is neededto identifythoseatriskofdevelopingestablishedrenalfailure.Theincreasedrelativeriskfordeath associatedwithlowerGFR(mostlyduetocardiovasculardisease)ismoreevidentinyounger people than in older people, largely because of fewer competing risks in younger people 2 patientsagedover75yearswithmoderateeGFR4560mL/minute/1.73m wereatnohigher risk of death over 13 years followup than their age peers with levels of eGFR above 60 2 13 mL/minute/1.73m .

ReducingtheRiskofProgressiveLossofGFR

Inadditiontospecifictherapytargetedattheunderlyingprimarydisease,recognitionoftherole ofseveralmodifiablesecondaryfactorsassociatedwithprogressivekidneydamageisimportant clinically, as these can be treated effectively thereby minimizing renal injury. Most of these interventionsalsoreducetheriskofcardiovasculardisease. SystemicHypertension Thetwomaingoalsofantihypertensivetherapyarecardiovasculardiseaseriskmodificationand reductionofriskofprogressivedeclineinGFR. Thereisstrongevidencethathighbloodpressure(BP)isassociatedwithincreasedriskbothof cardiovascular disease and of progressive kidney disease, and that these risks are higher amongstpeoplewithdiabetesthaninnondiabeticsubjectsatanygivenlevelofkidneyfunction. Several randomized controlled trials have shown that the risks of cardiovascular events and progressivekidneydiseasearereducedbyBPloweringtreatment.However,studiescomparing differentinterventionthresholds,differentBPtargets,anddifferentstrategiesforpatientswith varying degrees of proteinuria, comorbidity, and conduit artery compliance or pulse pressure arestillrequired.Twoimportantstudiestargetedmeanarterialpressureratherthansystolicor 14,15 diastolic, in contrast to current clinical practice. Many of the existing guidelines, therefore, arebasedonposthocanalysesofrandomizedcontrolledtrialsandobservationalstudies,and oftranslationofmeanarterialpressuresintosystolicanddiastolicpressures.Asaresult,there isconsiderableconfusionbetweenthevariousguidelinesandauditmeasurescurrentlyusedin theUK.WesuggestfollowingtherecommendationsbytheRenalAssociationandNICE(Figure 1). AccordingtoBritishHypertensionSocietyguidelinesandNICEguidance,thethresholdBPfor intervention is 140/90 mm Hg for patients with CKD without diabetes, and130/80 mm Hg for patientswithCKDanddiabetes.ThetargetBPtobeachievedisdeterminedbythedegreeof proteinuriapresent.InpeoplewithCKDandaurineproteintocreatinineratioof100mg/mmol orlower,thetargetBPissystolicbloodpressurelessthan140mmHg(targetrange120139 mm Hg) and thediastolic blood pressurebelow90 mm Hg. In patients with CKDand aurine proteintocreatinineratiomorethan100mg/mmol,andforallpatientswithCKDanddiabetes, aimtokeepthesystolicbloodpressurebelow130mmHg(targetrange120129mmHg)and 4 thediastolicbloodpressurebelow80mmHg. Patientswithproteinuriahigherthan1g/daymay benefit from more rigorous BP control (< 125/75 mm Hg). Reduction of proteinuria is an additional therapeutic goal dietary salt restriction amplifies the antiproteinuric effect of 16 antihypertensivetherapy.

Currently, there is no good evidence to suggest that lowering BP below standard targets 17,18 reduces mortality or morbidity. There is some evidence that intensive BP lowering is of benefitinthosewhoarehighriskforcerebrovascularevents,butinotherpatientgroupsalower targetBPmaybeharmfulbecauseofimpairedperfusionofvitalorganstheseincludepatients who are at high risk of falls, especially those with postural hypotension, and those with 19 concomitant coronary artery and peripheral vascular disease. Patients with multiple co morbiditiesareunlikelytohavebeenincludedinmostoftheinformativerandomizedcontrolled trials. It is clear that antihypertensive therapy should be individualized for patients, having assessedtherisksandbenefitsofintensiveversusstandardBPcontrol,andtakenintoaccount the patients attitude to risk and medication. Given that arterial blood pressure is just one of severalriskfactorsforcardiovascularandkidneydisease,itwouldbemorelogicaltoadopta riskbasedapproachratherthanonebasedonseparatethresholdsforbloodpressure,serum cholesterol, etc using this approach, more intensive treatment to reduceblood pressure (and other risk factors) would be recommendedfor patientsathigher risk. This transition to a risk based approach to risk factor modification is under way in many national and international guidelinegroupsitislikelytoresultinmorecoherentguidelinesthatwillallowpatientsandtheir physicianstousetheevidencebasetocometoshareddecisionsonwhichtreatmentstouse. Suchanapproachislikelyalsotoimproveadherencetotreatment. ChoiceofAntihypertensiveAgents ACE inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) afford significant renal protection, in addition to that attributable to blood pressure lowering, and should be used as 6

firstlineagentsinallpatientswithdiabetes(withorwithoutevidenceofalbuminuria), 20 innon diabetic kidney disease with proteinuria (random urine protein to creatinine ratio > 100 21 22 mg/mmol) andinthosewithheartfailure. TheroleofACEIsandARBsinnondiabetickidneydiseasewithlesssevereproteinuriaisnot as well established although there is good evidence that these drugs reduce albumin 23 excretion, thebenefits in terms of hard clinical outcomes havenot been established. In the absence of diabetes and/or albuminuria/proteinuria, the NICE Clinical Guideline 34 for hypertensionshouldbeconsulted.Manypatientsneedmorethanoneagenttoachievetarget BPgoals.Nondihydropyridinecalciumchannelblockers,suchasverapamilanddiltiazem,have additional antiproteinuric effects and are preferred to the dihydropyridine agents, which may increase proteinuria. Many patients with CKD are fluid overloaded and may benefit from concomitantdiuretictherapy,preferablyaloopdiuretic,asthiazidediureticsarelesseffectiveat 2 GFRlessthan30mL/minute/1.73m . Blockers, blockers and sympathetic antagonists may be needed in patients with resistant hypertension(ie,BP>150/90mmHgdespitethreeclassesofantihypertensiveagents). CombinationACEIandARBTherapy ThereissomeevidencethatcombinationACEIandARBtherapyoffersagreaterreductionin 24 proteinuriacomparedwithmonotherapy. However,theCOOPERATEstudy,whichappeared tosupportdualtherapy,hasnowbeenwithdrawnaftertheresultsofanacademicinvestigation 25 indicatedseriousconcernssurroundingthispublication. TheONTARGETstudysuggeststhat combinationtherapyshouldbeusedwithcaution,especiallyinpatientswithvasculardisease, 26 owing to the greater risk of hypotensive symptoms, syncope and renal dysfunction. An international, doubleblinded, randomized, controlled trial is ongoing to assess the effect of 27 combination reninangiotensin system blockade on CKD in diabetics. Owing to the risks of seriousadverseeffects,dualblockadewithanACEIandanARBshouldonlybeinitiatedunder specialistsupervision. Patients commencing therapy with ACEIs or ARBs should have their serum creatinine and potassiumcheckedwithin2weeksofinitiationoftherapyandaftereveryincrementindosage.If theserumcreatininerisesbymorethan30%ortheGFRfallsbymorethan25%frombaseline, alternativecausesofadeteriorationinrenalfunctionshouldbeinvestigated,dosagereducedto that previously tolerated or the agent withdrawn, and an alternative antihypertensive agent deployed. A significant fall in kidney function during ACEI/ARB inhibition can indicate haemodynamically significant renal artery narrowing, but the selection of patients who will benefitfromrevascularizationremainsproblematic.

ReductionofIntraglomerularHypertension Proteinuric CKD (including diabetic nephropathy) is typically characterized by intraglomerular hypertension,causedbyalterationsintheregulationofvasculartoneintheafferentandefferent glomerulararterioles,permittinggreatertransmissionofsystemicpressuretotheglomerulus. This increase in intraglomerular pressure is thought to be a major cause of progressive glomerulardamage. Although reduction of systemic BP helps to limit damage, some antihypertensive drugs (including ACEIs, ARBs, and nondihydropyridine calcium channel blockers) directly reduce intraglomerular pressure by selective vasodilatation of the efferent arterioles, whereas others (includingdihydropyridinecalciumchannelblockers)mayincreaseintraglomerularpressureand worsenproteinuria.ThebenefitsofACEI/ARBtreatmentare,therefore,moreevidentifsystemic 28 bloodpressureremainshigherthanoptimal. InhibitionofRenalFibrosis ACEIs and ARBs may have additional beneficial effects in progressive CKD, by inhibiting the actions of angiotensin II on glomerular permeability and tubulointerstitial fibrosis. Several targetsforantifibroticagentshavebeenvalidatedincellularandanimalstudies,butprogressin translating these results to clinical practice has been disappointing. Nevertheless, drugs targetingthepathwaysofTGF,connectivetissuegrowthfactor,plateletderivedgrowthfactor, 29 KiRasandNFKBareallpossiblefuturetherapeuticagents. SmokingCessation 8

Populationbasedstudieshaveshownanassociationbetweentobaccosmokingandincreased incidenceofCKD.SmokinghasalsobeenshowntoincreasetheriskofprogressionofCKDto endstagerenaldisease(ESRD),aneffectindependentoftheprimaryrenaldisease.Thereis evidence that cessation of smoking reduces loss of kidney function amongst patients with progressiveCKD. CorrectionofObesity Weight loss has been shown to ameliorate obesityinduced glomerular hyperfiltration, and to decrease proteinuria in patients with chronic proteinuric nephropathies. Weight loss also reduces blood pressure, and the reductions are larger in patients taking antihypertensive treatment. Lastly, weight loss can improve glycaemic control amongst people with diabetes 30 mellitus. GlycaemicControl TheDiabetesControlandComplicationsTrial(DCCT)andtheUKPDStrialprovidedevidence thatimprovedglycaemiccontrolpreventsthedevelopmentofmicroalbuminuriaaswellasother microvascularcomplicationsinpatientswithtype1and2diabetesmellituslongtermfollowup suggests that improved glycaemic control may have longterm beneficial effects on 31 macrovasculardiseaseaswell. Itislessclearwhetherimprovedglycaemiccontrolslowsdown progressiverenalinjuryonceovertproteinuriahasdeveloped. The target HbA1cfor patients with CKD and diabetes continues to be debated. Although two large trials have found that intensive glucose control (target HbA1c < 6.5% < 47 mmol/mol) compared with standard glucose control is associated with a reduction in newonset 32,33 microalbuminuria and macroalbuminuria, and a reduction in the development of new or 32 worseningnephropathy, inneithertrialdidintensivecontrolhaveaneffectonthedoublingof 33 serumcreatinine.Intensivecontrolisalsoassociatedwithanincreasedriskofhypoglycaemia, 34 which is associated with an increased risk of death. We would advise that clinicians individualizetherapyafterdiscussionwithpatients,takingintoaccountlifeexpectancy,overall cardiovascularandrenalrisk,aimingforatargetHbA1coflessthan7.5%(<58mmol/mol)for most. TreatmentofDyslipidaemia Dyslipidaemiaisariskmarkerforprogressivekidneyinjuryandariskfactorforcardiovascular disease.CurrentevidencethattreatmentofdyslipidaemiareducesCKDprogressionismostly restricted to post hoc subgroup analyses from large cardiovascular clinical trials, such as the Heart Protection study and the Cholesterol and Recurrent Events (CARE) study, where renal function was not the primary outcome studied. Results from the Study of Heart and Renal Protectiontrial(SHARP)haverecentlyprovidedevidencethatreducingserumLDLcholesterol (usingacombinationofsimvastatinandezetimibe)significantlyreducedtheincidenceofmajor atherosclerotic events (myocardial infarction, stroke and revascularization), with no adverse 35 effects. The size of the risk reduction was similar in patients with CKD and in patients on 36,37 dialysis.Previoustrialsofcholesterolloweringtherapiesinpatientswithkidneydisease were notabletodemonstratebenefit,possiblybecausetheylackedpowerorincludedalargenumber ofnonatheroscleroticcardiovascularevents,suchassuddencardiacdeathandhaemorrhagic strokeparticularly common in patients with established renal failure. The SHARP study 9

showednosignificantdifferenceinthenumberofpatientswithCKDreachingestablishedrenal failure. PharmacologicalManagement Many watersoluble drugs are cleared by the kidney and accumulate in CKD as a result of impaired excretion. For drugs with a high therapeutic index, reduced excretion is seldom a probleminstage3CKD,butcanbecomeimportantinstages4and5.Whenusinganestimate ofGFRtodecideondrugdosageadjustmentsinpatientsattheextremesofbodysize,itisalso importanttorememberthattheMDRDformulagivesanormalizedestimateofGFR(ie,whatthe 2 GFRwouldbeifthepatienthadanormalbodysurfaceareaof1.73m thisisthebestoverall measureoftheadequacyofrenalexcretoryfunction,becausemetabolicratethustheneedfor excretionofwasteproductsvarieswithbodysize). ActualGFR(whichdeterminesdrugclearance)maybesignificantlylowerthannormalizedGFR in small patients, and vice versa. Formulabased estimates of GFR should not, therefore, be usedtoadjustthedoseofrenallyexcreteddrugswithalowtherapeuticindex. The use of metformin presents particular problems, given the frequency with which CKD is foundamongstpeoplewithtype2diabetes.Metformincancausetype2lacticacidosis,andthe riskofthisveryrarecomplicationisprobablygreateramongstpatientswithreducedGFR.For thisreason,thesummaryofproductcharacteristicssuggeststhatthedrugisavoidedinpatients whoseserumcreatinineconcentrationis>150mol/L.However,thiscorrespondstoaneGFR 2 2 of67mL/minute/1.73m inayoungblackman,buttoaneGFRof33mL/minute/1.73m inan elderlywhitefemale. This illustrates the dangers of using serum creatinine concentration as the basis for drug dosageadjustment.Itwouldbepreferabletoreachadecisionthatbalancesriskandbenefitfor eachpatient,basedonthebestavailableestimateofthatpatientsactualGFR. Nephrotoxic drugs are more likely to cause a clinically important reduction in GFR if GFR is alreadysignificantlyreduced. AvoidingHaemodynamicInsults The classical model of progressive, proteinuric CKD (for which diabetic nephropathy is the exemplar)doesnotfullyexplaintheepidemiologyofCKDinparticular,itisinconsistentwiththe frequencyofstablestage3and4CKD. The existence of so many patients with stable but significant kidney damage suggests an alternativemodel,inwhichkidneyfunctiondeterioratesasaresultofaseriesofstepwisehits caused by episodes of nephrotoxicity, renal underperfusion, or renal atheromatous embolism. Clinical management of patients with CKD should, therefore, include precautions to minimize the risk of such insults. Patients taking ACEIs or ARBs should be advised to stop these temporarilyduringepisodesofdiarrhoeaand/orvomiting,andduringseveresepsis.Evenmore care should be taken in patients taking combinations of ARBs and ACEIs, as these agents significantly reduce the autoregulation of renal blood flow during episodes of renal underperfusion. 10

TreatmentofAcidosis There is increasing evidence from a number of small trials that alkali therapy in the form of sodiumbicarbonateorsodiumcitrateslowstherateofprogressionofrenalfailure,delaysthe 3840 development of established renal failure and improves nutritional status. Although larger, randomized,controlledtrialsarerequiredtosupportthis,alkalitherapyappearstobeofbenefit 40 at all stages of CKD regardless of the presence or absence of metabolic acidosis. Supplementationwithsodiumbicarbonate(typically1.53.0g/day)isreasonable. AnapproachtocommonuraemicsymptomsisoutlinedinTable1. FollowupandPreparationforRenalReplacementTherapy PatientswithCKDshouldbeofferedlifelongfollowuptoensureoptimalmanagement(asset outabove)andtomonitorchangesinkidneyfunction. SuggestedfrequencyoffollowupisgiveninTable2. The great majority of patients with CKD stage 3 will not progress to established renal failure and, even among CKD stage 4 patients, death from cardiovascular disease is more frequent than progression to established renal failure. However, there is evidence that patients who requirerenalreplacementtherapyhaveincreasedmorbidityandreducedsurvival,andaremore 41,42 expensivetomanageiftheypresenttoanephrologistlateintheirillness. Itisessentialthat thosewhoareatriskofprogressivedeclineinrenalfunctionareidentifiedearlyandreferredto secondary care. NICE recommends that the following patients should be referred to a 4 consultantnephrologist :

stage4or5CKD heavy proteinuria (urine albumin to creatinine ratio 70 mg/mmol urine protein to creatinine ratio 100 mg/mmol) unless known to result from diabetes and already appropriatelytreated proteinuria (urine albumin to creatinine ratio 30 mg/mmol urine protein to creatinine ratio50mg/mmol)ifaccompaniedbyhaematuria 2 2 rapidlydecliningeGFR(>5mL/minute/1.73m in1year,or>10mL/minute/1.73m within5years) hypertension that remains poorly controlled despite the use of at least four antihypertensivedrugsattherapeuticdosage peoplewithorsuspectedofhavingrareorgeneticcausesofCKD suspectedrenalarterystenosis.

DeclarationofInterests None. References

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18. Cushman WC, Evans GW, Byington RP, et al ACCORD Study Group. Effects of intensive blood pressurecontrolintype2diabetesmellitus.NEnglJMed2010362:15751585. 19. Bevry AA, Anderson RD, Gong Y, et al. Outcomes among hypertensive patients with concomitant peripheralandcoronaryarterydisease:findingsfromtheInternationalVerapamilSR/TrandolaprilStudy. Hypertension201055:4853. 20.StrippoliGFM,CraigME,CraigJC,LvJ,PerkovicV.Antihypertensiveagentsforpreventingdiabetic kidneydisease.CochraneDatabaseSysRev2005(4):CD004136. 21. Jafar TH, Stark PC, Schmid CH, et al. Progression of chronic kidney disease: the role of blood pressurecontrol,proteinuria,andangiotensinconvertingenzymeinhibition:apatientlevelmetaanalysis. AnnInternMed2003139:244252. 22. National Institute for Clinical Excellence CG108 chronic heart failure management of chronic heart failureinadultsinprimaryandsecondarycareAugust2010. 23. Asselbergs FW, The Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators. Effects of fosinopril and pravastatin on cardiovascular events in subjects withmicroalbuminuria.Circulation2004110:28092816. 24. Kunz R, Friedrich C, Wolbers M, Mann JF. Metaanalysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008148:3048. 25. Editors of the Lancet. Retractioncombination treatment of angiotensin II receptor blocker and angiotensin converting enzyme inhibitor in nondiabetic renal disease (COOPERATE): a randomized controlledtrial.Lancet2009374:1226. 26. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in peopleathighvascularrisk(theONTARGETstudy):amulticentre,randomised,doubleblind,controlled trial.Lancet2008372:547553. 27.ParvingHH,BrennerBM,McMurrayJJ,etal.AliskirenTrialinType2DiabetesUsingCardioRenal EndpointsALTITUDE:rationaleandstudydesign.NephrolDialTransplant200924:16631671. 28. Ruggenenti P, Perna A, Benini R, RemuzziG. Effects of dihydropyridine calcium channel blockers, angiotensinconverting enzyme inhibition, and blood pressure control on chronic, nondiabetic nephropathies. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). J Am Soc Nephrol 19989:20962101. 29. Boors P, Ostendorf T, Floege J. Renal fibrosis: novel insights into mechanisms and therapeutic targets.NatRevNephrol20106:643656. 30. Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction on blood pressureametaanalysisofrandomisedcontrolledtrials.Hypertension200342:878884. 31. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10year followup of intensive glucose controlintype2diabetes.NEnglJMed2008359:15771589. 32.PatelA,MacMahonS,ChalmersJ,etal.Intensivebloodglucosecontrolandvascularoutcomesin patientswithtype2diabetes.NEnglJMed2008358:25602572.

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33.GersteinHC,MillerME,ByingtonRP,etal.Effectsofintensiveglucoseloweringintype2diabetes.N EnglJMed2008358:25452559. 34.ZoungasS,PatelA,ChalmersJ,etalADVANCECollaborativeGroup.Severehypoglycaemiaand risksofvasculareventsanddeath.NEnglJMed2010363:14101418. 35.SHARPtrialwww.sharpinfo.org36.WannerC,KraneV,MrzW,etal.fortheGermanDiabetesand Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.NEnglJMed2005353:238248. 37. Fellstrm BC, Jardine AG, Schmieder RE, et al. for The AURORA Study Group. Rosuvastatin and cardiovasculareventsinpatientsundergoinghemodialysis.NEnglJMed2009360:13951407. 38. de BritoAshurst I, Varagunam M, Raftery MJ, Yaqoob MM. Bicarbonate supplementation slows progressionofCKDandimprovesnutritionalstatus.JAmSocNephrol200920:20752084. 39. Phisitkul S, Khanna A, Simoni J, et al. Amelioration ofmetabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR. Kidney Int 201077:617623. 40.MahajanA,SimoniJ,SheatherSJ,BroglioKR,RajabMH,WessonDE.Dailyoralsodiumbicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy. Kidney Int 201078:303309. 41. McClellan WM, Wasse H, McClellan AC, Kipp A, Waller LA, Rocco MV. Treatment center and geographic variability in preESRD care associate with increased mortality. J Am Soc Nephrol 200920:10781085. 42. Hasegawa T, BraggGresham JL, Yamazaki S, et al. Greater firstyear survival on hemodialysis in facilities in which patients are provided earlier and more frequent prenephrology visits. Clin J Am Soc Nephrol20094:595602.2011ElsevierLtd.InitiallypublishedinMedicine201139(7):407413. AbouttheAuthor Charlie Tomson is a Consultant Nephrologist at North Bristol NHS Trust, UK. As Chair of the Joint Specialty Committee on Renal Medicine of the Royal College of Physicians of London and the Renal Association,heledthedevelopmentofUKguidelinesfortheIdentification,Management,andReferralof Adults with Chronic Kidney Disease. His research interests include the causes of premature cardiovascular disease in patients with kidney disease, and quality improvement in healthcare. He is currentlyPresidentoftheRenalAssociation.PippaBaileyisanAcademicClinicalFellowinNephrology atSouthmeadHospital,Bristol,UK.

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