開同專家會議

Ketoacidtherapyand

CKDmetaboliccomplications3rdInternationalKetoanaloguesymposiumSeoul,March30-31,2007M.AparicioM.D

IntroductionCRFresultsinnumerousmetabolicdisorderswhichaccountforseverecomplicationsresponsibleformajormorbidityandmortalitycondition.PreventionofthesecomplicationsshouldbetheaimwhilemanagingCKDpatientsinordertoimproveausuallypooroutcome.PhysiopathologyofmetabolicdisordersinCRF°Accumulationofwasteproductsusuallyexcretedbythekidneys:-nitrogenouswasteproducts,H+ions,phosphate….°Iontransportabnormalities

°Decreasedhormoneproduction:-EPO,calcitriol°Decreasedhormoneclearance:-insulin,glucagon,leptin°InflammationWhybeneficialeffectsonmetabolicdisorderscanbeexpectedfromSVLPD

SVLPDpermitstherestrictionoftheintakeoroftheproductionofnitrogenouswasteproducts,phosphate,inorganicionsandhydrogenions.SVLPDimprovesNa+K+ATPaseactivityinCRFpatientsLastly,itislikelythatSVLPDiseffectiveincorrectinginflammationassuggestedbyrecentnutritionalinterventionsusingaconventionalLPDorMediterranean-styledietCaloricsupply

(kcal/kgbw/day)30-35%fromcarbohydrates67%fromlipids30%fromproteins

3Proteincontent

(g/kgbw/day)0.3-0.4(max.0.6)Phosphoruscontent

(mg/kgbw/day)5-7Supplementedwith:Calcium(g/day)0.5-1.0VitaminD(IU/day)1,000Iron(mg/day)100mg/kgbw/day10-15DietarymanagementinCKDCompositionofaKetoAcidTherapyKA/AA(Ketosteril?)EffectsofSVLPDon

carbohydratemetabolismdisorders

InsulinresistanceinCKDpatients

OccursearlyinthecourseofCRFandispresentinmorethan50%ofCKDpatients.Isfavouredby:-accumulationofproteinwasteproducts-metabolicacidosis-inflammation-2ndHPTInsulinresistanceinCKDpatientseffectsoncarbohydratemetabolismInsulinresistance:-decreasedglucosestorage-decreasedglucoseoxidation-increasedendogenousglucoseproduction

-

decreasedmetabolicclearancerateofinsulin-elevatedfastingglucoseandinsulinlevels

Insulinresistancein

typeIIdiabetesandinCRFtypeIIdiabetesCRFglycemia+++insulinlevels++++glucosestorage----glucoseoxidation--EGP++++Invivoexploration

ofglucosemetabolism:thetoolsOralglucosetolerancetest:overallglucosemetabolismHyperinsulinemiceuglycemicclamp:insulinsensitivity,MCRofexogenousinsulinConcomitantuseofindirectcalorimetry:oxidativeandnonoxidativepathwayofglucoseIsotopicallylabeledglucose:endogenousglucoseproduction

PlasmaglucoseandInsulinafteroralglucoseloadbeforeandafter3monthsonSVLPDL.Bailletetcol.,Metabolism2001EvolutionoftheinsulinlevelandoftheamountglucoseinfusedduringtheeuglycemichyperinsulinclampinnondiabeticuremicpatientsbeforeandafterSVLPDAparicioM.etal.KidneyInt,1989KetoAcidsTherapyimprovesthemetabolicclearancerateofinsulinandreduceshyperinsulinemiawhichisassociatedwithmultipleriskfactorsforatherosclerosis

GINH.etalAm.J.Clin.Nutr.1994

KetoAcidTherapyImprovementofinsulinclearancerateSVLPDandsubstrateoxidationrate

RigalleauKidneyInt.1997

baselinemonth3glucoseoxidationmg/kg/min1.46+/-0.311.71+/-0.28lipidoxidationmg/kg/min0.79+/-0.081.02+/-0.01proteinoxidationmg/kg/min0.29+/-0.060.07+/-0.01energyproductioncal/kg/min15.72+/-0.4817.16+/-0.67REEandSVLPDinuremiaRigalleauKidneyInt.1997SVLPDandendogenousglucose

production(EGP)RigalleauAm.J.Clin.Nutr.1997baselinemonth3insulinMCR(mL/min)803+/-2041149+/-284EGP(mg/kg/min)0.90+/-0.310.30+/-0.17Insulinresistance:othereffects

IndependentCVriskfactor:-endothelialdysfunction(decreasedendothelialNOsynthesis),improvementinIRimprovesendothelialfunction-atherosclerosisProteinmetabolism:-increasedskeletalmuscleproteinbreakdown(UPP)Inflammation:-subclinicalinflammationispartofIRsyndromeCopyright?2002AmericanSocietyofNephrologyShinohara,K.etal.JAmSocNephrol2002;13:1894-1900InsulinresistanceandoutcomeofESRDpatientsMechanismsofimprovementof

insulinresistancebySVLPDDecreasedaccumulationofnitrogenouscompoundsactingasinhibitorsofglucoseutilizationImprovementofmetabolicacidosisImprovementof2ndHPTDirectbeneficialeffectofproteinrestrictiononglucosemetabolismwhenproteincaloriesaremadeupbycarbohydratecaloriesEffectsofSVLPDon

secondaryhyperparathyroidismFactorsof2ndHPTHyperphosphatemiaDecreasedcalcitriolsynthesisNegativecalciumbalanceMetabolicacidosisPCaHighphosphatelevelsLowcalciumlevelsPhosphate-CalciummetabolismdisordersinCKDConsequencesof2ndHPT

andhyperphosphatemiaOsteodystrophyCardiovascularcalcificationSofttissuecalcificationRefractoryanemiaInflammationIncreaseintherelativeriskofdeath*p<0.05Design:No.ofpatients:n=17(GFR

20ml/min) Duration: 12months Diet: 0.3gprotein/kgbw/d+1tabl.Ketosteril?/5kgbw/d +1gCaCO3

+1,000IUvitaminD2LAFAGEetal.(1992):KidneyInt,42,1217-1225KetoAcidTherapyPhosphate-Calciummetabolismdisordersp<0.01*Parameters(mean+SD)NormalrangeBeforethedietAfter12monthsofdietCalcium(mmol/l)2.1-2.652.29±0.152.32±0.16Phosphate(mmol/l)0.8-1.451.54±0.421.30±0.28(a)Bicarbonate(mmol/l)24-3023.1±4.627.6±3(c)IntactPTH(μg/ml)10-60168±10183±68(b)Alk.Phophatase(IU/l)30-12088±4586±38Osteocalcin(μg/ml)3.7-6.940±2931±251-25OHVitaminD(pg/ml)12.-3215.3±6.817.5±6.9LAFAGEetal.(1992):KidneyInt,42,1217-1225Resultsareexpressedasmean+SD:(a)p<0.05;(b)p<0.01;(c)p<0.001KetoAcidTherapyPhosphate-CalciummetabolismdisordersDesign:No.ofpatients:n=21 Creatinineserum:>6.5mg/dl Diet: VLPD(0.3g/kgbw/d)+AA/KA+2-4gCaCO3 Duration: 42months

PTHlevelcanbereducedby49%duetothedietarytherapy.BARSOTTIetal.(1998):sHPTinsevereCRFiscorrectedbyvery-lowdietaryphosphateintakeandcalciumcarbonatesupplementation.Nephron,79,137-141*p<0.001*p<0.001KetoAcidTherapyPhosphate-CalciummetabolismdisordersKetoAcidTherapyPhosphate-CalciummetabolismdisordersImprovementinosteofibroticandosteomalacicchangesafter

12monthsoftreatmentwithaKetoAcidTherapy.

M.HLafageetal.KidneyInt.1992KetoAcidTherapyPhosphate-CalciummetabolismdisordersEvolutionofhistologicaldata

after12monthsonSVLPD

M.H.Lafageetal.KidneyInt.1992Mixedosteopathy(n=4):-mineralizationrate(u/d):0.32+/-0.15to0.67+/-0.02-osteoidthickness(u):13+/-2.5to8+/-2-BFR(u3/u2/d):0.005+/-0.006to0.044+/-0.02Osteitisfibrosa(n=9):-osteoblasticsurface(%):8.4+/-2.6to6+/-3.1-osteoclasticsurface(%):7.7+/-2.8to3.1+/-2.2-BFR(u3/u2/d):0.087+/-0.43to0.044+/-0.03Mechanismsofimprovementof

2ndHPTbySVLPDReducedphosphateintake(1gprotein=13mgP)ImprovementofmetabolicacidosisCasaltsofketoacids:-increasedCaintake-actasphosphatebindersEffectsofSVLPDonmetabolicacidosisFixedacidproductionApproximately1mmolacid/kgbodyweightisgeneratingeverydaybyadultseatinga?

regulardiet

?Fish,meat,grainproductsandcheeseshaveahighpotentialrenalacidload.Incontrast,fruitsandvegetablessupplyalkali-ashMetabolicacidosisinCRFpathogenesisDecreasedabilitytoexcretenonvolatilacidsReducedrenalsynthesisofbicarbonateMetabolicacidosisinCRF

consequences-I-Nutritionalstatus:-increasedproteincatabolism-decreasedmuscleproteinandalbuminsynthesis-negativenitrogenandtotalbodyproteinbalanceBonemetabolism:-inhibitionofosteoblastandstimulationofosteoclastfunction-releaseofcalciumandphosphatetobufferH+ionsMetabolicacidosisinCRF

consequences-II-InducesinsulinresistanceImpairstriglyceridesutilizationPlasmabicarbonatelevelsanddeathrateinHDpatientsLowrie-LewAJKD1990

KetoAcidTherapyCorrectionofmetabolicacidosisCorrelationbetweenthechangesinbicarbonatelevelsandthechangesofthemineralappositionrate

M.H.LafageKidneyInt.1992

EffectsofSVLPDonlipiddisorders°HYPERTRIGLYCERIDAEMIA

(duetotheimpairmentoftriglyceridehydrolysis)°DYSLIPOPROTEINAEMIA-DecreaseinHDL-cholesterol

(mostimportantantiatherogenicfactor)-IncreaseofapolipoproteinCIII-DecreaseinapolipoproteinAI(integralpartofHDL)°

NEPHROTICSYNDROME

-IncreaseintotalandLDL-cholesterol1)BERNARDetal.(1996):MinerElectrolyteMetab,22,143-146;2)CIARDELLAetal.(1988):Nephron,42,196-199;3)ATTMANandALAUPOVIC(1991):Nephron,51,401-410LipidmetabolismdisordersinCKDDyslipidemiamayhavearoleinthecardiovasculardiseasewhichisresponsibleof50%ofdeathsafterinitiatingmaintenancedialysistherapySeveralreportshavesuggestedthatdyslipidemiamightfavourtheprogressionofrenalfailureConsequencesoflipiddisordersinCRFSignificantimprovementoftheserumlipidprofile

-Correctionofhypertriglyceridaemia(211+/-139vs.154+/-102mg/dl;p<0.05)Ciardellaetal.Nephron1986

-IncreaseinserumapolipoproteinAI(1.73+/-0.05vs.1.82+/-0.06g/l;p<0.025)Bernardetal.Miner.ElectrolyteMetab.1996-IncreaseinHDL-cholesterol(35.1+/-8.1vs.45.7+/-12.2mg/dl;p<0.005)AttmanandAlaupovicNephron1991

-Decrease

intotalcholesterol(5.9+/-1.4vs5.2+/-1.2mmol/L;p<0.01)Chauveauetal.J.Ren.Nutr.2007KetoAcidTherapyOverallimprovementoflipidmetabolismOutcomeofproteinuriaaccordingtobaselinevalues

allpatientsn=781-3g/24