A New Perspective on Chronic Kidney Disease

A New Perspective on ChronicA New Perspective on Chronic
Kidney DiseaseKidney Disease
by Steve Chenby Steve Chen
Director of Nephrology,
Shin-Chu Branch of Taipei Veterans General Hospital

CKD: chronic kidney diseaseCKD: chronic kidney disease

Team care for CKD: staged goalsTeam 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

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 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？ )

CKD, stage IICKD, stage II~~III: risk of CVDIII: risk of CVD
Pinkau 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 CVD
Pinkau 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 stageCKD stage ≧≧III: risk (AHR) of CHFIII: risk (AHR) of CHF
Coresh et al: JASN 2007 (ARIC: Johns Hopkins University SchoolCoresh 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) inSBP: 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

Lipoprotein metabolism in CKDLipoprotein metabolism in CKD
Cheung 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 ↑↑↗ －↓ ↑

TGTG ↑↑in uremiain uremia
Cheung 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 metabolicTiming of onset of CKD-related metabolic
complicationscomplications
Olivier Moranne et al: JASN 20: 164-171, 2009 (France)

Metabolic acidosis:Metabolic acidosis: HCO3HCO3 ≧≧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 CKD
Kurtz 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 metabolicHCO3 therapy in severe metabolic
acidosisacidosis
 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 CKD
Gennari 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/DOQICKD: 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(OH)Vitamin-D3 indications25(OH)Vitamin-D3 indications
Cannata-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/ml
259OH)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 CKDVitamin D mean level in CKD
P. Ravani et al: KI 75: 88-95, 2009(Italy)
N=168

Development & progression of SHPTDevelopment & 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 inHypo-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 1.52
Model 2 989 1 1.21 1.60
Model 3 848 1 1.17 1.56
Model 1: adjusted for age, gender, and race
Model 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 survivalOral 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 0.12
Model 2 0.67 <0.001 0.73 0.003
Model 3 0.74 0.016 0.80 0.038
As-treated model
0.76 0.044 0.80 0.06
Model 1: adjusted for age, gender, and race
Model 2: further adjusted for baseline PTH, e GFR, DM, CAD, Charlson comorbidity index
Model 3: adds ACEI, ARB, Statin, ESA or oral Calcium user; BMI, SBP, S-Albumin
As-treated model censors control patients at first oral cacitriol prescription
Shoben et al: JASN 19: 1613-1619, 2008

Renal anemia: Hb < 11 g/dlRenal 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&prepub
ertal
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 CKD
Frederick 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 ↑

Dietary control in CKD patientsDietary 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 & 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

Dietary protein intake for non-dialysisDietary protein intake for non-dialysis
PTSPTS
K-DOQI guidelines
GFR < 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-dialysisDietary energy intake for non-dialysis
PTSPTS
K/DOQI guidelines
Stage 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 CKD
Teplan 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 EPOETINCell 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

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

TREATTREAT
A trial of darbapoetin alfa on DM and CKD
N > 4000
Achieved 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 withMortality risk associated with
higher Hemoglobin: Hb>12higher Hemoglobin: Hb>12

Normal target: ↑CV riskNormal target: ↑CV risk

CV risk↑
Blood viscosity↑
Post-dialysis
Hemo-concentration
Oxidative stress
IV 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 for2012 KDIGO guidelines for
anemia in CKDanemia in CKD
2012 Kidney Disease: Improving Global Outcomes

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-β1
Khwaja 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 mitogensCKD: Proliferative mitogens
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: ISACKD: ISA
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 transduction
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 future
Pentoxyfylline 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 Experimental
Tocopherols Antioxidant Clinical trial in CKD

Pentoxyphylline on proteinuria in DNPentoxyphylline on proteinuria in DN
McCormick 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 onPTX in addition to Losartan on
UP/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/D
for CKD-4 ～ 5
PTX 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)

Initiation of dialysisInitiation of dialysis
SJ Rosansky et al: KI 76: 257-261,2009

A New Perspective on Chronic Kidney Disease

A New Perspective on Chronic Kidney Disease

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