A New Perspective on Chronic A New Perspective on Chronic Kidney Disease Kidney Disease

by Steve Chenby Steve Chen

Director of Nephrology, Shin-Chu Branch of Taipei Veterans General Hospital

CKD: chronic kidney disease CKD: chronic kidney disease

Team Care

Team care for CKD: staged goals Team care for CKD: staged goals

GFR*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

Team care for CKD: multidisciplinaryTeam care for CKD: multidisciplinary分類GFR

Stage I

＞ 90

Stage II

60~90

Stage III

30~60

Stage IV

15~30　　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

X

X

X

X

X

X

X

X

X

X

X

X

X

CKD 病患

ESRD

III b <45

Eye risk factors

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

Obesity: risk for CKD/FLDObesity: risk for CKD/FLD

Joachim H.Lx et al: JASN 21: 406-412, 2010

Chronic kidney disease/Fatty liver disease

Time for renal consult and referral Time 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？ )

Be watchful for CV dangers

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

GFR↓

S-Cr ↑

↑Adjusted CV risk

Healthy 10 ml/min per 1.73m2

0.1 mg/dl

5%

4%

LVH 10 ml/min per 1.73m2 19%

1.CABG

2.PTCA

1. Bypass Angioplasty Revascularization Investigation (BARI) 2000

2. Best et al, JACC 2002

1. Independent predictor of mortality 2. Independent predictor of mortality and subsequent cardiac events

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 PTS S-Cr > 133 μmol/L: ↑2.8X adjusted major CVD risk

HOPE study: N= 9297 CAD or DM+1 CV risk factor S-Cr > 124 μmol/L( 1.4 mg/dl) : ↑1.7 X adjusted CV mortality

CKD stage CKD stage ≧≧III: risk (AHR) of CHFIII: risk (AHR) of CHFCoresh et al: JASN 2007 (ARIC: Johns Hopkins University School Coresh et al: JASN 2007 (ARIC: Johns Hopkins University School

of Medicine Baltimoreof Medicine Baltimore))

0

0.5

1

1.5

2

2.5

3

>90 60-90 <60

No CHD

CHD

All

SBP: J-shaped stroke risk (AHR) in SBP: J-shaped stroke risk (AHR) in CKD IIICKD III ～～ IVIV

Sarnak et al: JASN 2007 ( Tufts-New England Medical Center)Sarnak et al: JASN 2007 ( Tufts-New England Medical Center)

0

0.5

1

1.5

2

2.5

3

3.5

<120 120-129 130-139 140-159 >160

Non CKD

CKD

Further dangers on metabolism

Lipoprotein metabolism in CKDLipoprotein metabolism in CKDCheung et al: JASN 2007Cheung et al: JASN 2007

CKD NS HD PD

TC ↑↑ ↗ －↓ ↑LDL-C ↑↑ ↗ －↓ ↑HDL-C ↓ ↓ ↓ ↓

Non-HDL-C ↑↑ ↗ －↓ ↑ TG ↑↑ ↑ ↑↗

Lp (a) ↑↑ ↑ ↑↑↗

Apo A-I ↓ ↓↘ ↗

Apo A-IV ↑ ↑ ↑↗ ↘

Apo B ↑↑ ↗ －↓ ↑

TG ↑in uremiaTG ↑in uremiaCheung et al: JASN 2007Cheung et al: JASN 2007

↓CHO tolerance

↑Hepatic synthesis of VLDL

↑TG

Heparin in HD↑Apo CIII/CII

Plasma lipase inhibitors

↓LPL↓HTGL

↓Fractional catabolism of TG

Timing of onset of CKD-related metabolic Timing of onset of CKD-related metabolic complicationscomplications

Olivier Moranne et al: JASN 20: 164-171, 2009 (France)

Metabolic acidosis: Metabolic acidosis: HCO3 HCO3 ≧≧2222

[HCO3] = 23.7- [Scr] x 0.6 If S-Cr 4~5 mg/dl

S-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/L

CAPD: lactate based dialystae: 35 meq/L or 25 meq/L HCO3+15 meq/L lactate

Non calcium phosphate binder/sevelamer: not suggested!

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 Comments Muscle wasting Even in mind CKD; Major factor

Reduced albumin synthesis One of many factors

Bone disease Contributory not primary factor

Impaired insulin sensitivity Effect unclear: seem in syndrome X

β2Microglobulin accumulation Found in dialysis patients

Exacerbation of renal failure Data for and against

Impaired thyroid metabolism Contribute to abnormality in BMR

Stunted growth Reversed in part by correction of acidosis

Cardiac disease Theoretical not proven

Increased inflammation Evidence for and against

HCO3 therapy in severe metabolic HCO3 therapy in severe metabolic acidosis acidosis

Optimal extracellular pH= 7.4; Optimal intracellular pH=7.1

HCO3 therapy is recommended at an arterial pH 6.9 ~ 7.2 ( 7.0); but efforts focused on reversing the underlying defects responsible for acidosis

Volume of distribution of HCO3: 50% ~ >100% of total body water HCO3 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

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:

DM Tubulo-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/L

Acute intervention reserved in SK> 6.5meq/L

CKD: K/DOQI CKD: K/DOQI

CKD 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 35-70

IV 15-29 2.7-4.6 8.4-10.2 70-100

V <15 3.5-5.5 8.4-9.5 <55 150-300

25(25(OH)Vitamin-D3 indicationsOH)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 (inverse

relation)25(OH)D3 deficiency: < 10ng/ml259OH)D3 insufficiency: 10 ～ 30ng/ml 25(OH)D3>18-20ng/ml: adequate if elderly

health 25(OH)D3 sufficiency >30ng/ml: 29% in

CKD-III; 17% CKD-IV Sharon et al: AJKD 2005

Vitamin D mean level in CKD Vitamin D mean level in CKD

P. Ravani et al: KI 75: 88-95, 2009(Italy)

N=168

Development & progression of SHPT Development & progression of SHPT >60 pg/ml in CKD>60 pg/ml in CKD

PTH secretion

Pre-pro-PTH gene transcription/synthesis

Parathyroid cell proliferation

Ca SR

VDR

Hypo-VD <15: Mortality in Hypo-VD <15: Mortality in non-dialyzed CKDnon-dialyzed CKD

Parameter Total events Vitamin D N=1418 >30 15-30 <15

Model 1 1123 1 1.18 1.52Model 2 989 1 1.21 1.60Model 3 848 1 1.17 1.56 Model 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 ratio Model 3: further adjusted for Hb, S-Alb, S-Pi, education, income, medical insulance R Mehrotra et al: KI 76: 977-983, 2009

Oral calcitriol improve survival Oral calcitriol improve survival in non-dialyzed CKDin non-dialyzed CKD

Parameter Mortality Mortality or long-term dialysis N=1418 Adjusted HR / P Adjusted HR / P

Model 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 model 0.76 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 prescription Shoben et al: JASN 19: 1613-1619, 2008

Renal anemia: Hb < 11 g/dl Renal anemia: Hb < 11 g/dl Iseki 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-Gault Hct = 38.6% ~ 38.95%

Growth failure in CKDGrowth failure in CKD(<3rd percentile for age) :(<3rd percentile for age) :3030~~50%50%

Onset age Clinical degree Interventions

<3Y IUGR

Further loss in <1Y

Growth preserved later

Early nutritional support

Prevention of metabolic defects

>3Y GFR>25

Maintain growth rate along the initial trajectory

rh-GH

>3Y&prepubertal

GFR<25

Further height loss < 0.2 SD/year

Peak velocity of puberty: 2.5 years of delay

Final adult height, compromised : 50%

rh-GH :

0.05 mg/Kg/D x 6M

0.06mg/Kg/D, later

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 ↑

Treatments = Challenges

Dietary control in CKD patients Dietary control in CKD patients

Advantages Disadvantages

Proven Decreased toxin load Predisposition to PEM Slowing progression Complex diet Better BP control Need for close supervision Better Pi control Decreased muscle mass Better H control Improved insulin sensitivity Improved UP in NS patients

Controversial Extending time to ESRD Possible weight gain Increased mortality (VLPD)

Targets for protein & Targets for protein & energyenergy ：：

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

Dietary protein intake for non-dialysis Dietary protein intake for non-dialysis PTS PTS

K-DOQI guidelinesGFR < 25 ml/min

0.6~0.75 G/Kg/D Stage I~III

0.75G/Kg/D Very low protein diet (0.28~0.3 G/Kg/D)+

keto-acid supply (0.3G/Kg/D)

Dietary energy intake for non-dialysis Dietary energy intake for non-dialysis PTSPTS

K/DOQI guidelinesStage 4~5

35Kcal/Kg/D if age < 60 30~35 Kcal/Kg/D if age ≧ 60

25~35 Kcal/Kg/D for Taiwanese

38

Where are other targets set?

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 <125/75 mmHg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

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

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 %

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

Cell effect of EPOETIN Cell effect of EPOETIN Rossert 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 and renal endothelial cells Westenfelder et al, KI 55: 808-820, 1999

Renal (GFR 10 ml/min) anemia ( Hct 26.8%): N=83 Target Hct 35% at W 16 GFR decline: -0.13 ml/min/M vs -0.39

44

What level do we get at ?

ACORD trial: diabetic CKD 1ACORD trial: diabetic CKD 1 ～～ 33

N= 172 Group 1: target H-b 13 ～ 15 g/dl

Group II: target H-b 10.5 ～ 11.5 g/dl Primary end point: LVMI No significant difference in median LVMI at month

15 No effect on rate of decrease in C-Cr Prevention of an additional increase of LVMI:Safe

CREATE trialCREATE trial CREATE (Cardiovascular Risk Reduction by

Early Anemia Treatment with Epoetin beta): randomized clinical trial

N= 600 Among subjects who achieved their randomized

target, a benefit on CV outcome or death associated with higher Hb goal( Hb>12 g/dl) was not detected

Hb < 12 G/dl ?

CHOIR trial: CKD IIICHOIR trial: CKD III ～～ IVIV N= 1290 in 4-M landmark analysis; 1056 in 9-M

analysis Inclusion criteria: CKD/GFR 15 ～ 50 ml/min

with Hb < 11 g/dl Randomized to Hb targets of 11.3 or 13.5 mg/dl

using different dosing algorithms Primary end point: death, MI, CHF, or stroke Patients achieving their target has better outcome Among subjects who achieved their randomized

target, increased risk associated with higher Hb goal was detected

TREATTREATA trial of darbapoetin alfa on DM and CKDN > 4000Achieved HB:

12.5 g/dl in treatment Gr 10.6g/dl in placebo Gr

Primary outcome: death + nonfatal CV event + ESRD No decrease

Increased risk of stroke: 5.0%/2.6%(2X)

Chen CY et al: NEJM 2009; 361(21): 2019-2032

Mortality risk associated with Mortality risk associated with higher Hemoglobin: Hb>12 higher Hemoglobin: Hb>12

Normal target: ↑CV riskNormal target: ↑CV risk

CV risk↑

Blood viscosity↑

Post-dialysis Hemo-concentration

Oxidative stressIV iron

Direct effect↑BP

2007 FDA black-box warnings for ESA2007 FDA black-box warnings for ESA

Use the lowest dose of ESA that will gradually increase the Hb to the lowest level sufficient to avoid the need for blood transfusion

Eryhtropoiesis-stimulating agents (ESA) increase the risk of death and for serious CV events when administered to target a Hb 12 g/dl≧

A recommendation to withhold, not reduce ESA dose when Hb is greater than 12 g/dl

2012 KDIGO guidelines for 2012 KDIGO guidelines for anemia in CKDanemia in CKD

2012 Kidney Disease: Improving Global Outcomes

53

Probe further

CKD: mechanismsCKD: mechanisms

Injury

Kidney cell

Necrosis/apoptosis

Atrophy

EMT: embryonic phenotype

Myofibroblast

Proliferation & Migration

ECM ↑Synthesis ↓Clearance

Fibrosis

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 level

BMP-7 ↓ TGFβ1-Smad pathway Experimental HGF ↓ Nuclear translocation of Trials in promoting

receptor-regulated Smads angiogenesis

↑Smads corepressors

Mediator X ↓ TGFβ1-induced fibrosis Phase II in DN

Tranilast ↓TGFβ1-induced ECM synthesis Clinical data in DN

Used in hypertrophic scars and scleroderma Decorin Sequesters TGFβ1 in ECM Experimental

CKD: Proliferative mitogens CKD: Proliferative mitogens Khwaja et al: KI 2007 (Northern General Hospital, UK)Khwaja et al: KI 2007 (Northern General Hospital, UK)

Mechanism Evidence level

Anti-PDGF PDGF aptamers

Imatinib Kinase inhibitors of PDGF transduction Cardiotoxicity limit use

CR002 Monoclonal Ab-PDGF Phase I trial in MPGN

Trapidil

Anti-EGF ↓ Renal fibroblast Experimental

CKD: ISA CKD: ISA Khwaja et al: KI 2007 (Northern General Hospital, UK)Khwaja et al: KI 2007 (Northern General Hospital, UK)

Mechanism Evidence level

MMF Inhibitors of IMP dehydrogenase No clear data in CKD

↓ cell proliferation Rapamycin Ribosomal biogenesis and protein translation

cell proliferation No clear data in CKD

But ↑proteinuria

CKD: intracellular transductionCKD: intracellular transductionKhwaja et al: KI 2007 (Northern General Hospital, UK)Khwaja et al: KI 2007 (Northern General Hospital, UK)

Mechanism Evidence level

1>↓Ras-Raf-Mek-Erk pathway Experimental (↓Cell proliferation, differentiation, apoptosis)

Statins Ras prenylation inhibitors Not yet defined Prenyl-transferase inhibitors/Raf/Mek kinase inhibitors

2> 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

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 proteinuric CKD

EMT PPARγ agonists ↓Cell growth Clinical trail in CKD

↓Inflammation Proteinuria in DN↓

Endothelin antagonists ↓ Cell proliferation

↓ Intra-G HTN Clinical trial in DN

Pirfenidone ↓ ECM Phase II in DN

Prolyl hydroxylase domain inhibitors Experimental Cobalt chloride ↑VEGF ↑EPO

N-acetyl-cysteine Antioxidant ExperimentalTocopherols Antioxidant Clinical trial in CKD

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 with

placebo: weighted mean difference -278 mg/D ( p<0.001)

Compared with ACEI, UP reduction with PTX is similar

Secondary analysis: UP> 300md/D: PTX weighted mean difference -502 mg/D ( p=0.001)

PTX in addition to Losartan on PTX in addition to Losartan on UP/GFR in CKDUP/GFR in CKD

A 12-M RCT: N=85CKD 3 with UP > 500md/D≧PTX: 400mg x 2/D for CKD-3; 400mg/D

for CKD-4 ～ 5PTX reduce UP with mean change -23.9%

compared with control: 13.8%; group difference 38.7% ( p<0.001) Lin et al: AJKD 2008 (NTUH)

To shift or undergo dialysis

Initiation of dialysis Initiation of dialysis

SJ Rosansky et al: KI 76: 257-261,2009