开同专家会议.pptx

KetoacidtherapyandCKDmetaboliccomplications3rdInternationalKetoanaloguesymposiumSeoul,March30-31,2007M.AparicioM.DIntroductionCRFresultsinnumerousmetabolicdisorderswhichaccountforseverecomplicationsresponsibleformajormorbidityandmortalitycondition.PreventionofthesecomplicationsshouldbetheaimwhilemanagingCKDpatientsinordertoimproveausuallypooroutcome.PhysiopathologyofmetabolicdisordersinCRFAccumulationofwasteproductsusuallyexcretedbythekidneys:-nitrogenouswasteproducts,H+ions,phosphate.IontransportabnormalitiesDecreasedhormoneproduction:-EPO,calcitriolDecreasedhormoneclearance:-insulin,glucagon,leptinInflammationWhybeneficialeffectsonmetabolicdisorderscanbeexpectedfromSVLPDSVLPDpermitstherestrictionoftheintakeoroftheproductionofnitrogenouswasteproducts,phosphate,inorganicionsandhydrogenions.SVLPDimprovesNa+K+ATPaseactivityinCRFpatientsLastly,itislikelythatSVLPDiseffectiveincorrectinginflammationassuggestedbyrecentnutritionalinterventionsusingaconventionalLPDorMediterranean-styledietCaloric supply(kcal/kg bw/day)30-35%from carbohydrates67%from lipids30%from proteins 3Protein content (g/kg bw/day)0.3-0.4(max.0.6)Phosphorus content (mg/kg bw/day)5-7Supplemented with:Calcium(g/day)0.5-1.0Vitamin D(IU/day)1,000Iron(mg/day)100 mg/kg bw/day10-15Dietary management in CKDComposition of a Keto Acid TherapyKA/AA(Ketosteril)EffectsofSVLPDoncarbohydratemetabolismdisordersInsulinresistanceinCKDpatientsOccursearlyinthecourseofCRFandispresentinmorethan50%ofCKDpatients.Isfavouredby:-accumulationofproteinwasteproducts-metabolicacidosis-inflammation-2ndHPTInsulinresistanceinCKDpatientseffectsoncarbohydratemetabolismInsulinresistance:-decreasedglucosestorage-decreasedglucoseoxidation-increasedendogenousglucoseproduction-decreasedmetabolicclearancerateofinsulin-elevatedfastingglucoseandinsulinlevelsInsulinresistanceintypeIIdiabetesandinCRFtypeIIdiabetesCRFglycemia+insulinlevels+glucosestorage-glucoseoxidation-EGP+Invivoexplorationofglucosemetabolism:thetoolsOralglucosetolerancetest:overallglucosemetabolismHyperinsulinemiceuglycemicclamp:insulinsensitivity,MCRofexogenousinsulinConcomitantuseofindirectcalorimetry:oxidativeandnonoxidativepathwayofglucoseIsotopicallylabeledglucose:endogenousglucoseproductionPlasma glucose and Insulin after oral glucose load before and after 3 months on SVLPD L.Baillet et col.,Metabolism 2001EvolutionoftheinsulinlevelandoftheamountglucoseinfusedduringtheeuglycemichyperinsulinclampinnondiabeticuremicpatientsbeforeandafterSVLPDAparicioM.etal.KidneyInt,1989 Keto Acids Therapy improves the metabolic clearance rate of insulin and reduces hyperinsulinemia which is associated with multiple risk factors for atherosclerosis GIN H.et al Am.J.Clin.Nutr.1994 Keto Acid TherapyImprovement of insulin clearance rateSVLPDandsubstrateoxidationrateRigalleauKidneyInt.1997baselinemonth3glucoseoxidationmg/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.1997SVLPDandendogenousglucoseproduction(EGP)RigalleauAm.J.Clin.Nutr.1997baselinemonth3insulinMCR(mL/min)803+/-2041149+/-284EGP(mg/kg/min)0.90+/-0.310.30+/-0.17Insulinresistance:othereffectsIndependentCVriskfactor:-endothelialdysfunction(decreasedendothelialNOsynthesis),improvementinIRimprovesendothelialfunction-atherosclerosisProteinmetabolism:-increasedskeletalmuscleproteinbreakdown(UPP)Inflammation:-subclinicalinflammationispartofIRsyndromeCopyright 2002 American Society of NephrologyShinohara,K.et al.J Am Soc Nephrol 2002;13:1894-1900Insulin resistance and outcome of ESRD patientsMechanismsofimprovementofinsulinresistancebySVLPDDecreasedaccumulationofnitrogenouscompoundsactingasinhibitorsofglucoseutilizationImprovementofmetabolicacidosisImprovementof2ndHPTDirectbeneficialeffectofproteinrestrictiononglucosemetabolismwhenproteincaloriesaremadeupbycarbohydratecaloriesEffectsofSVLPDonsecondaryhyperparathyroidismFactorsof2ndHPTHyperphosphatemiaDecreasedcalcitriolsynthesisNegativecalciumbalanceMetabolicacidosisPCaHigh phosphate levelsLow calcium levelsPhosphate-Calcium metabolism disorders in CKDConsequencesof2ndHPTandhyperphosphatemiaOsteodystrophyCardiovascularcalcificationSofttissuecalcificationRefractoryanemiaInflammationIncreaseintherelativeriskofdeath*p 0.05Design:No.of patients:n=17(GFR 20 ml/min)Duration:12 months Diet:0.3 g protein/kg bw/d+1 tabl.Ketosteril/5 kg bw/d +1 g CaCO3+1,000 IU vitamin D2LAFAGE et al.(1992):Kidney Int,42,1217-1225Keto Acid TherapyPhosphate-Calcium metabolism disordersp 0.01*Parameters(mean+SD)Normal rangeBefore the dietAfter 12 months of dietCalcium(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)Intact PTH(g/ml)10-60168 10183 68(b)Alk.Phophatase(IU/l)30-12088 4586 38Osteocalcin(g/ml)3.7-6.940 2931 251-25 OH Vitamin D(pg/ml)12.-3215.3 6.817.5 6.9LAFAGE et al.(1992):Kidney Int,42,1217-1225Results are expressed as mean+SD:(a)p 0.05;(b)p 0.01;(c)p 6.5 mg/dl Diet:VLPD(0.3 g/kg bw/d)+AA/KA+2-4 g CaCO3 Duration:4 2 months PTH level can be reduced by 49%due to the dietary therapy.BARSOTTI et al.(1998):sHPT in severe CRF is corrected by very-low dietary phosphate intake and calcium carbonate supplementation.Nephron,79,137-141*p 0.001*p 0.001Keto Acid TherapyPhosphate-Calcium metabolism disordersKeto Acid TherapyPhosphate-Calcium metabolism disordersImprovement in osteofibrotic and osteomalacic changes after 12 months of treatment with a Keto Acid Therapy.M.H Lafage et al.Kidney Int.1992Keto Acid TherapyPhosphate-Calcium metabolism disordersEvolutionofhistologicaldataafter12monthsonSVLPDM.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+/-0.03Mechanismsofimprovementof2ndHPTbySVLPDReducedphosphateintake(1gprotein=13mgP)ImprovementofmetabolicacidosisCasaltsofketoacids:-increasedCaintake-actasphosphatebindersEffectsofSVLPDonmetabolicacidosisFixedacidproductionApproximately1mmolacid/kgbodyweightisgeneratingeverydaybyadultseatingaregulardietFish,meat,grainproductsandcheeseshaveahighpotentialrenalacidload.Incontrast,fruitsandvegetablessupplyalkali-ashMetabolicacidosisinCRFpathogenesisDecreasedabilitytoexcretenonvolatilacidsReducedrenalsynthesisofbicarbonateMetabolicacidosisinCRFconsequences-I-Nutritionalstatus:-increasedproteincatabolism-decreasedmuscleproteinandalbuminsynthesis-negativenitrogenandtotalbodyproteinbalanceBonemetabolism:-inhibitionofosteoblastandstimulationofosteoclastfunction-releaseofcalciumandphosphatetobufferH+ionsMetabolicacidosisinCRFconsequences-II-InducesinsulinresistanceImpairstriglyceridesutilizationPlasmabicarbonatelevelsanddeathrateinHDpatientsLowrie-LewAJKD1990Keto Acid TherapyCorrection of metabolic acidosisCorrelationbetweenthechangesinbicarbonatelevelsandthechangesofthemineralappositionrateM.H.LafageKidneyInt.1992EffectsofSVLPDonlipiddisorders HYPERTRIGLYCERIDAEMIA (due to the impairment of triglyceride hydrolysis)DYSLIPOPROTEINAEMIA -Decrease in HDL-cholesterol(most important antiatherogenic factor)-Increase of apolipoprotein C III -Decrease in apolipoprotein A I(integral part of HDL)NEPHROTIC SYNDROME -Increase in total and LDL-cholesterol1)BERNARD et al.(1996):Miner Electrolyte Metab,22,143-146;2)CIARDELLA et al.(1988):Nephron,42,196-199;3)ATTMAN and ALAUPOVIC(1991):Nephron,51,401-410Lipid metabolism disorders in CKDDyslipidemia may have a role in the cardiovasculardisease which is responsible of 50%of deaths after initiating maintenance dialysis therapy Several reports have suggested that dyslipidemia might favour the progression of renal failureConsequences of lipid disorders in CRF Significant improvement of the serum lipid profile -Correction of hypertriglyceridaemia(211+/-139 vs.154+/-102 mg/dl;p 0.05)Ciardella et al.Nephron 1986 -Increase in serum apolipoprotein A I(1.73+/-0.05 vs.1.82+/-0.06 g/l;p 0.025)Bernard et al.Miner.Electrolyte Metab.1996 -Increase in HDL-cholesterol(35.1+/-8.1 vs.45.7+/-12.2 mg/dl;p 0.005)Attman and Alaupovic Nephron 1991 -Decrease in total cholesterol (5.9+/-1.4 vs 5.2+/-1.2 mmol/L;p 3g/24hn=22T02.76+/-1.31.83+/-0.54.98+/-2.2T12.04:74%1.51:82%3.40:68%T31.37:51%1.0:52%2.33:45%T61.59:58%1.07:58%2.93:58%T121.91:69%1.23:67%3.89:78%Correlationbetweenoutcomeofproteinuriaandofserumcholesterol4567Chol0Chol1Chol3Chol6Chol9Chol124567Chol0Chol1Chol3Chol6Chol9Chol12patientswithproteinuria3g/dayatstartpatientswithreductionofproteinuria50%AntiproteinurictreatmentandoutcomeoftotalserumcholesterolNavisContribNephrol1997MechanismsofimprovementoflipiddisordersbySVLPDDecreasedproductionofnitrogenouswasteproductsthatmayactasinhibitorsoflipaseactivityCorrectionofinsulinresistanceParallelreductioninproteinintakefromanimalsourceandintheassociatedsaturatedlipidsImprovementoflipidprofileinresponsetoareductioninproteinuriaConclusionNumerousstudieshaveconfirmedtheefficacyofSVLPDonmostofthemetabolicdisorderslinkedtoCRF.TheseeffectsaccountfortheimprovementoftheoutcomeofCKDpatientsandforthesubstantialdelayintheinitiationofRRTwhichhavebeenreportedinmostseries.