A New Perspective on Chronic Kidney Disease

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  • A New Perspective on Chronic Kidney Disease

    1. 1. A New Perspective on ChronicA New Perspective on ChronicKidney DiseaseKidney Diseaseby Steve Chenby Steve ChenDirector of Nephrology,Shin-Chu Branch of Taipei Veterans General Hospital
    2. 2. CKD: chronic kidney diseaseCKD: chronic kidney disease
    3. 3. Team Care
    4. 4. Team care for CKD: staged goalsTeam care for CKD: staged goalsGFR*ml/min/1.73m2 分 類  目 標 (Goals)Serum Cr(mg/dl) 追 蹤 (F-U)≧ 90 微量尿蛋白 衛教病患腎臟病之觀念 ♂ ︰ 1.5≧♀ ︰ 1.2≧每半年60 ~ 89 輕度腎衰竭( CRI )阻緩腎功能惡化之各種治療方式 ♂ ︰≧ 1.5♀ ︰≧ 1.2每半年30 ~ 59 中度腎衰竭( CRF )衛教病患接受尿毒症之觀念 ♂ ︰ 2.0 ~6.0♀ ︰ 1.5 ~6.0每 3 個月15 ~ 29 重度腎衰竭( Pre-ESRD)建立血管通路之時機6.0 ~ 8.0每 1~3 個月< 15 末期腎臟疾病( ESRD )開始透析治療或腎移植> 8.0 ~10.0每 2~4 星期
    5. 5. Team care for CKD: multidisciplinaryTeam care for CKD: multidisciplinary分類GFRStage I> 90Stage II60~90Stage III30~60Stage IV15~30  目標 診斷及治療原發病因腎臟病之介紹腎臟疾病之分期阻緩腎功能惡化營養不良 蛋白質攝取尿毒症觀念減少心血管疾病之合併症建立血管通路腎臟替代療法衛教小組腎臟專科醫師衛教護理師營養師XXXXXXXXXXXXXCKD 病患ESRDIII b <45
    6. 6. Eye risk factors
    7. 7. CKD: risk factorsCKD: risk factors 透析病患與慢性腎臟病病患 18 歲以上二等親家屬 吸煙 高蛋白飲食 特定職業者:客車駕駛 男性 Obesity(BMI ≧ 27):Metabolic syndrome( 代謝症候群 ) 糖尿病 高血脂症 高血壓
    8. 8. Obesity: risk for CKD/FLDObesity: risk for CKD/FLDJoachim H.Lx et al: JASN 21: 406-412, 2010Chronic kidney disease/Fatty liver disease
    9. 9. Time for renal consult and referralTime for renal consult and referralRenal consult( 照會腎臟專科醫師 )NIH consensus statement on morbidity and mortality of dialysis (USA, 1994)Serum Cr ≧ 1.5 mg/dl ( 女性 )≧ 2.0 mg/dl ( 男性 )腎臟專科醫師追蹤時機 : 每 3 ~ 6 個月Renal referral( 腎臟專科醫師接手 )Serum Cr 4.0 mg/dl (DM≧ 應較早? )
    10. 10. Be watchful for CV dangers
    11. 11. CKD, stage IICKD, stage II~~III: risk of CVDIII: risk of CVDPinkau et al, JASN 15: 517-523, 2004Pinkau et al, JASN 15: 517-523, 2004GFR↓S-Cr ↑↑Adjusted CV riskHealthy 10 ml/min per 1.73m20.1 mg/dl5%4%LVH 10 ml/min per 1.73m2 19%1.CABG2.PTCA1. Bypass AngioplastyRevascularizationInvestigation (BARI) 20002. Best et al, JACC20021. Independent predictor ofmortality2. Independent predictor ofmortality and subsequentcardiac events
    12. 12. CKD, stage IICKD, stage II~~III: risk of CVDIII: risk of CVDPinkau et al, JASN 15: 517-523, 2004Pinkau et al, JASN 15: 517-523, 2004HOT study: N=18790 HTN PTSS-Cr > 133 μmol/L: ↑2.8X adjustedmajor CVD riskHOPE study: N= 9297 CAD or DM+1 CVrisk factorS-Cr > 124 μmol/L( 1.4mg/dl) : ↑1.7 X adjusted CV mortality
    13. 13. CKD stageCKD stage ≧≧III: risk (AHR) of CHFIII: risk (AHR) of CHFCoresh et al: JASN 2007 (ARIC: Johns Hopkins University SchoolCoresh et al: JASN 2007 (ARIC: Johns Hopkins University Schoolof Medicine Baltimoreof Medicine Baltimore))00.511.522.53>90 60-90 <60No CHDCHDAll
    14. 14. SBP: J-shaped stroke risk (AHR) inSBP: J-shaped stroke risk (AHR) inCKD IIICKD III ~~ IVIVSarnak et al: JASN 2007 ( Tufts-New England Medical Center)Sarnak et al: JASN 2007 ( Tufts-New England Medical Center)00.511.522.533.5<120 120-129 130-139 140-159 >160Non CKDCKD
    15. 15. Further dangers on metabolism
    16. 16. Lipoprotein metabolism in CKDLipoprotein metabolism in CKDCheung et al: JASN 2007Cheung et al: JASN 2007CKD NS HD PDTC ↑↑↗ -↓ ↑LDL-C ↑↑↗ -↓ ↑HDL-C ↓ ↓ ↓ ↓Non-HDL-C ↑↑↗ -↓ ↑TG ↑↑ ↑ ↑↗Lp (a) ↑↑ ↑ ↑↑↗Apo A-I ↓ ↓↘ ↗Apo A-IV ↑ ↑ ↑↗ ↘Apo B ↑↑↗ -↓ ↑
    17. 17. TGTG ↑↑in uremiain uremiaCheung et al: JASN 2007Cheung et al: JASN 2007↓CHO tolerance↑Hepatic synthesisof VLDL↑TGHeparin in HD↑Apo CIII/CIIPlasma lipase inhibitors↓LPL↓HTGL↓Fractional catabolismof TG
    18. 18. Timing of onset of CKD-related metabolicTiming of onset of CKD-related metaboliccomplicationscomplicationsOlivier Moranne et al: JASN 20: 164-171, 2009 (France)
    19. 19. Metabolic acidosis:Metabolic acidosis: HCO3HCO3 ≧≧2222[HCO3] = 23.7- [Scr] x 0.6 If S-Cr 4~5 mg/dlS-HCO3= 20.7~ 21.3 meq/L K/DOQI guideline: S-HCO3 up to 22 meq/L CARD (Australians) guidelines: 23 ~ 24 meq/L HD: dialysate base HCO3 39 ~ 40 meq/LCAPD: lactate based dialystae: 35 meq/L or 25meq/L HCO3+15 meq/L lactate Non calcium phosphate binder/sevelamer: notsuggested!
    20. 20. Metabolic acidosis in CKDMetabolic acidosis in CKDKurtz et al: AJKD 2005(David Geffen School of Medicine, LA)Kurtz et al: AJKD 2005(David Geffen School of Medicine, LA)Effect CommentsMuscle wasting Even in mind CKD; Major factorReduced albumin synthesis One of many factorsBone disease Contributory not primary factorImpaired insulin sensitivity Effect unclear: seem in syndromeXβ2Microglobulin accumulation Found in dialysis patientsExacerbation of renal failure Data for and againstImpaired thyroid metabolism Contribute to abnormality in BMRStunted growth Reversed in part by correction of acidosisCardiac disease Theoretical not provenIncreased inflammation Evidence for and against
    21. 21. HCO3 therapy in severe metabolicHCO3 therapy in severe metabolicacidosisacidosis Optimal extracellular pH= 7.4; Optimal intracellularpH=7.1 HCO3 therapy is recommended at an arterial pH 6.9 ~ 7.2( 7.0); but efforts focused on reversing the underlyingdefects responsible for acidosis Volume of distribution of HCO3:50% ~ >100% of total body waterHCO3 space: (0.4+2.6/PHCO3) by Fernandez Assume arterial pH will not change; Target pH=7.2 No hard and fast rule works for every patient
    22. 22. Hyper-K>5.0 meq/L in CKDHyper-K>5.0 meq/L in CKDGennari et al, KI 62: 1-9, 2002Gennari et al, KI 62: 1-9, 2002 Prevalence( SK> 5.0meq/L): 55% Risk factors:DMTubulo-interstitial disease Hyper-K even in mild-moderate CKD:SCr 2-4mg/dl Muscle K↑; total K↓: loss of muscle Adaptive response: 5.0-5.5meq/LAcute intervention reserved in SK> 6.5meq/L
    23. 23. CKD: K/DOQICKD: K/DOQICKD GFR Pi(mg/dl)Ca(mg/dl)Ca x Pi i PTH(pg/ml)III 30-59 2.7-4.6 8.4-10.2 35-70IV 15-29 2.7-4.6 8.4-10.2 70-100V <15 3.5-5.5 8.4-9.5 <55 150-300
    24. 24. 25(OH)Vitamin-D3 indications25(OH)Vitamin-D3 indicationsCannata-Andia et al, NDT, 2002Cannata-Andia et al, NDT, 200225(OH)D3<5-7ng/ml: osteomalacia25(OH)D3<10-12ng/ml: 2’ HPT (inverserelation)25(OH)D3 deficiency: < 10ng/ml259OH)D3 insufficiency: 10 ~ 30ng/ml25(OH)D3>18-20ng/ml: adequate if elderlyhealth25(OH)D3 sufficiency >30ng/ml: 29% inCKD-III; 17% CKD-IVSharon et al: AJKD 2005
    25. 25. Vitamin D mean level in CKDVitamin D mean level in CKDP. Ravani et al: KI 75: 88-95, 2009(Italy)N=168
    26. 26. Development & progression of SHPTDevelopment & progression of SHPT>60 pg/ml in CKD>60 pg/ml in CKDPTH secretionPre-pro-PTH genetranscription/synthesisParathyroid cell proliferationCa SRVDR
    27. 27. Hypo-VD <15: Mortality inHypo-VD <15: Mortality innon-dialyzed CKDnon-dialyzed CKDParameter Total events Vitamin DN=1418 >30 15-30 <15Model 1 1123 1 1.18 1.52Model 2 989 1 1.21 1.60Model 3 848 1 1.17 1.56Model 1: adjusted for age, gender, and raceModel 2: further adjusted for smoking, HTN, history of CVD, BMI, DM, family history,non-HDL-C>160, CRP,CKD stage, Urine Albumin-Cr ratioModel 3: further adjusted for Hb, S-Alb, S-Pi, education, income, medical insulance RMehrotra et al: KI 76: 977-983, 2009
    28. 28. Oral calcitriol improve survivalOral calcitriol improve survivalin non-dialyzed CKDin non-dialyzed CKDParameter Mortality Mortality or long-termdialysisN=1418 Adjusted HR / P Adjusted HR / PModel 1 0.76 0.014 0.86 0.12Model 2 0.67 <0.001 0.73 0.003Model 3 0.74 0.016 0.80 0.038As-treated model0.76 0.044 0.80 0.06Model 1: adjusted for age, gender, and raceModel 2: further adjusted for baseline PTH, e GFR, DM, CAD, Charlson comorbidity indexModel 3: adds ACEI, ARB, Statin, ESA or oral Calcium user; BMI, SBP, S-AlbuminAs-treated model censors control patients at first oral cacitriol prescriptionShoben et al: JASN 19: 1613-1619, 2008
    29. 29. Renal anemia: Hb < 11 g/dlRenal anemia: Hb < 11 g/dlIseki et al, NDT 18: 899-905, 2003Iseki et al, NDT 18: 899-905, 2003Hematocrit (%)= C-Cr x 0.0704 +37.194If C-Cr: 20~25 ml/min by Cockcroft-GaultHct = 38.6% ~38.95%
    30. 30. Growth failure in CKDGrowth failure in CKD(<3rd percentile for age) :(<3rd percentile for age) :3030~~50%50%Onset age Clinical degree Interventions<3Y IUGRFurther loss in <1YGrowth preserved laterEarly nutritional supportPrevention of metabolicdefects>3YGFR>25Maintain growth ratealong the initialtrajectoryrh-GH>3Y&prepubertalGFR<25Further height loss < 0.2SD/yearPeak velocity of puberty:2.5 years of delayFinal adult height,compromised : 50%rh-GH :0.05 mg/Kg/D x 6M0.06mg/Kg/D, later
    31. 31. Growth failure in CKDGrowth failure in CKDFrederick Kaskel, KI 64: 1141-51, 2003Frederick Kaskel, KI 64: 1141-51, 2003 ↑GH, pulsate release ↑GH level IGF-1 not increased ↓Hepatic synthesis of IGF-1 ↓bioavailability of IGF-1 due to ↓IGFBP-3 ↓GH receptor density in tibial growth plate ↓mRNA of hepatic GH receptor ↓Post-receptor signal transduction Glucose infusion → GH secretion ↑
    32. 32. Treatments =
    33. 33. Dietary control in CKD patientsDietary control in CKD patientsAdvantages DisadvantagesProven Decreased toxin load Predisposition to PEMSlowing progression Complex dietBetter BP control Need for close supervisionBetter Pi control Decreased muscle massBetter H controlImproved insulin sensitivityImproved UP in NS patientsControversial Extending time to ESRD Possible weight gainIncreased mortality (VLPD)
    34. 34. Targets for protein & energyTargets for protein & energy ::限制蛋白飲食限制蛋白飲食< 0.6 ~ 0.8 g/kg/day高生物價值蛋白:如蛋白,牛奶足夠熱量 : > 35 kcal/kg/day配合 Keto acid 或必須胺基酸低磷飲食
    35. 35. Dietary protein intake for non-dialysisDietary protein intake for non-dialysisPTSPTSK-DOQI guidelinesGFR < 25 ml/min0.6~0.75 G/Kg/DStage I~III0.75G/Kg/DVery low protein diet (0.28~0.3 G/Kg/D)+keto-acid supply (0.3G/Kg/D)
    36. 36. Dietary energy intake for non-dialysisDietary energy intake for non-dialysisPTSPTSK/DOQI guidelinesStage 4~535Kcal/Kg/D if age < 6030~35 Kcal/Kg/D if age ≧ 6025~35 Kcal/Kg/D for Taiwanese
    37. 37. 38Where areothertargetsset?
    38. 38. Targets for BPTargets for BP血壓控制血壓控制嚴格控制血壓 : BP <130/80 mmHg有蛋白尿 > 1 g/24h 者 : BP <125/75mmHg血管張力素轉化脢抑制劑 (ACEI)– 具長期腎臟保護作用– 除了降壓效果外,主要是其降低蛋白尿效果– 初期使用,血清肌酸酐可能上升( < 30% ),若持續上升,或 [K+] > 5.5 mEq/L 則須停藥
    39. 39. Targets for lipidsTargets for lipids控制高血脂症控制高血脂症理由:防止加速性動脈血管硬化及腎絲球傷害降血脂有助於降低血壓目標 LDL < 100 mg/dL飲食,減重, statins 藥物
    40. 40. Targets for blood sugarTargets for blood sugar控制血糖控制血糖糖尿病患者,嚴格控制血糖,延緩腎病變,神經病變,血管病變目標: Hb A1c < 7 %
    41. 41. Metabolic effect of EPO in CKDMetabolic effect of EPO in CKDTeplan et al, AJKD 41: S26-S30, 2003Teplan et al, AJKD 41: S26-S30, 2003Shift protein balance to anabolism↓Anaerobic glycolysis and pyruvate-mediated gluconeogenesis→ BCAA ↑↑Transamination of essential keto&hydroxy analogues↑Plasma lipoprotein lipase & liver lipase↑Physical activity; ↑HDL-C
    42. 42. Cell effect of EPOETINCell effect of EPOETINRossert et al, JASN 14: S173-177, 2003Rossert et al, JASN 14: S173-177, 2003 Increased number of Red cells→ oxygen delivery↑→ protection against oxidative stress ↑ Anti-apoptotic effects on renal PCT cells andrenal endothelial cellsWestenfelder et al, KI 55: 808-820, 1999 Renal (GFR 10 ml/min) anemia ( Hct 26.8%):N=83Target Hct 35% at W 16GFR decline: -0.13ml/min/M vs -0.39
    43. 43. 44What level do weget at ?
    44. 44. ACORD trial: diabetic CKD 1ACORD trial: diabetic CKD 1 ~~ 33 N= 172 Group 1: target H-b 13 ~ 15 g/dlGroup II: target H-b 10.5 ~ 11.5 g/dl Primary end point: LVMI No significant difference in median LVMI atmonth 15 No effect on rate of decrease in C-Cr Prevention of an additional increase of LVMI:Safe
    45. 45. CREATE trialCREATE trial CREATE (Cardiovascular Risk Reduction byEarly Anemia Treatment with Epoetin beta):randomized clinical trial N= 600 Among subjects who achieved their randomizedtarget, a benefit on CV outcome or deathassociated with higher Hb goal( Hb>12 g/dl) wasnot detected Hb < 12 G/dl ?
    46. 46. CHOIR trial: CKD IIICHOIR trial: CKD III ~~ IVIV N= 1290 in 4-M landmark analysis; 1056 in 9-Manalysis Inclusion criteria: CKD/GFR 15 ~ 50 ml/minwith Hb < 11 g/dl Randomized to Hb targets of 11.3 or 13.5 mg/dlusing different dosing algorithms Primary end point: death, MI, CHF, or stroke Patients achieving their target has better outcome Among subjects who achieved their randomizedtarget, increased risk associated with higher Hbgoal was detected
    47. 47. TREATTREATA trial of darbapoetin alfa on DM and CKDN > 4000Achieved HB:12.5 g/dl in treatment Gr10.6g/dl in placebo GrPrimary outcome: death + nonfatal CVevent + ESRD No decrease Increased risk of stroke: 5.0%/2.6%(2X)Chen CY et al: NEJM 2009; 361(21): 2019-2032
    48. 48. Mortality risk associated withMortality risk associated withhigher Hemoglobin: Hb>12higher Hemoglobin: Hb>12
    49. 49. Normal target: ↑CV riskNormal target: ↑CV riskCV risk↑Blood viscosity↑Post-dialysisHemo-concentrationOxidative stressIV ironDirect effect↑BP
    50. 50. 2007 FDA black-box warnings for ESA2007 FDA black-box warnings for ESA Use the lowest dose of ESA that will graduallyincrease the Hb to the lowest level sufficient toavoid the need for blood transfusion Eryhtropoiesis-stimulating agents (ESA) increasethe risk of death and for serious CV events whenadministered to target a Hb 12 g/dl≧ A recommendation to withhold, not reduce ESAdose when Hb is greater than 12 g/dl
    51. 51. 2012 KDIGO guidelines for2012 KDIGO guidelines foranemia in CKDanemia in CKD2012 Kidney Disease: Improving Global Outcomes
    52. 52. 53Probe further
    53. 53. CKD: mechanismsCKD: mechanismsInjuryKidney cellNecrosis/apoptosisAtrophyEMT: embryonic phenotypeMyofibroblastProliferation & MigrationECM↑Synthesis ↓ClearanceFibrosis
    54. 54. CKD: a look into TGF-β1CKD: a look into TGF-β1Khwaja et al: KI 2007 (Northern General Hospital, UK)Khwaja et al: KI 2007 (Northern General Hospital, UK)Mechanism Evidence levelBMP-7 ↓ TGFβ1-Smad pathway ExperimentalHGF ↓ Nuclear translocation of Trials in promotingreceptor-regulated Smads angiogenesis↑Smads corepressorsMediator X ↓ TGFβ1-induced fibrosis Phase II in DNTranilast ↓TGFβ1-induced ECM synthesis Clinical data in DNUsed in hypertrophic scars and sclerodermaDecorin Sequesters TGFβ1 in ECM Experimental
    55. 55. CKD: Proliferative mitogensCKD: Proliferative mitogensKhwaja et al: KI 2007 (Northern General Hospital, UK)Khwaja et al: KI 2007 (Northern General Hospital, UK)Mechanism Evidence levelAnti-PDGFPDGF aptamersImatinib Kinase inhibitors of PDGF transduction Cardiotoxicity limit useCR002 Monoclonal Ab-PDGF Phase I trial in MPGNTrapidilAnti-EGF ↓ Renal fibroblast Experimental
    56. 56. CKD: ISACKD: ISAKhwaja et al: KI 2007 (Northern General Hospital, UK)Khwaja et al: KI 2007 (Northern General Hospital, UK)Mechanism Evidence levelMMF Inhibitors of IMP dehydrogenase No clear data in CKD↓ cell proliferationRapamycin Ribosomal biogenesis and protein translationcell proliferation No clear data in CKDBut ↑proteinuria
    57. 57. CKD: intracellular transductionCKD: intracellular transductionKhwaja et al: KI 2007 (Northern General Hospital, UK)Khwaja et al: KI 2007 (Northern General Hospital, UK)Mechanism Evidence level1>↓Ras-Raf-Mek-Erk pathway Experimental(↓Cell proliferation, differentiation, apoptosis)Statins Ras prenylation inhibitors Not yet definedPrenyl-transferase inhibitors/Raf/Mek kinase inhibitors2> Fasudil Rho kinase inhibitors Experimental(↓cell proliferation, tubulo-interstitial fibrosis)3> p38 mitogen activated protein kinase inhibitors(↓pro-inflammatory/pro-fibrotic mediators) Clinical trail in DM(1)4> Ruboxistaurin PKC inhibitors Clinical data in DN
    58. 58. CKD: a look into the futureCKD: a look into the futureKhwaja et al: KI 2007 (Northern General Hospital, UK)Khwaja et al: KI 2007 (Northern General Hospital, UK)Mechanism Evidence levelPentoxyfylline Cell proliferation Clinical trial in proteinuricCKDEMTPPARγ agonists ↓Cell growth Clinical trail in CKD↓Inflammation Proteinuria in DN↓Endothelin antagonists ↓ Cell proliferation↓ Intra-G HTN Clinical trial in DNPirfenidone ↓ ECM Phase II in DNProlyl hydroxylase domain inhibitors ExperimentalCobalt chloride ↑VEGF ↑EPON-acetyl-cysteine Antioxidant ExperimentalTocopherols Antioxidant Clinical trial in CKD
    59. 59. Pentoxyphylline on proteinuria in DNPentoxyphylline on proteinuria in DNMcCormick et al: AJKD 2008(University of Ottawa)McCormick et al: AJKD 2008(University of Ottawa) Meta-analysis: N=476 PTX significantly reduce UP compared withplacebo: weighted mean difference -278 mg/D( p<0.001) Compared with ACEI, UP reduction with PTX issimilar Secondary analysis:UP> 300md/D: PTX weighted meandifference -502 mg/D ( p=0.001)
    60. 60. PTX in addition to Losartan onPTX in addition to Losartan onUP/GFR in CKDUP/GFR in CKDA 12-M RCT: N=85CKD 3 with UP > 500md/D≧PTX: 400mg x 2/D for CKD-3; 400mg/Dfor CKD-4 ~ 5PTX reduce UP with mean change -23.9%compared with control: 13.8%; groupdifference 38.7% ( p<0.001)Lin et al: AJKD 2008 (NTUH)
    61. 61. To shift or undergo dialysis
    62. 62. Initiation of dialysisInitiation of dialysisSJ Rosansky et al: KI 76: 257-261,2009

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