hypertension and diabetic kidney disease progression hypertension and diabetic kidney disease...
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Hypertension and Diabetic Kidney Disease Progression
George L. Bakris, MDProfessor and Vice-Chairman Dept. of Preventive MedicineDirector, Hypertension/Clinical Research CenterRush University Medical CenterChicago, IL 60612
©2006. American College of Physicians. All Rights Reserved.
Disclosure of Relationships with Commercial Companies:
George L. Bakris, MD, FACP
Research Grants/Contracts: NIH (NIDDK/NHLBI), AstraZeneca, Abbott, Alteon, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Novartis, Lilly, Sankyo
Consultantship: Astra-Zeneca, AusAm, Abbott, Alteon, Biovail, Boehringer-Ingelheim, BMS/Sanofi, GlaxoSmithKline, Merck, Novartis, Lilly
Speakers Bureau: Boehringer-Ingelheim, BMS/Sanofi, GlaxoSmithKline, Merck, Novartis, Lilly
©2006. American College of Physicians. All Rights Reserved.
Increasing Prevalence of Diagnosed Diabetes in US Adults
Centers for Disease Control and Prevention Web site. Available at:http://www.cdc.gov/diabetes/statistics/prev/state/fig61994and2002.htm.
Accessed August 30, 2004.
1994 2002
<4% 4–4.9% 5–5.9% 6%
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Increasing Prevalence of Obesity* Among US Adults
Centers for Disease Control and Prevention Web site. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/index.htm.
Accessed August 30, 2004.
*BMI ≥ 30 kg/m2.
10%–14% 15%–19% 20%–24% ≥ 25%
1994 2002
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Walking the dog
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Incidence of Kidney Failureper million population, 1990, by HSA, unadjusted
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Incidence of Kidney Failureper million population, 2000, by HSA, unadjusted
Incidence of Kidney Failureper million population, 2000, by HSA, unadjusted
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Diabetes:Diabetes:The Most Common Cause of ESRDThe Most Common Cause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Diabetes50.1%
Hypertension27%
Glomerulonephritis
13%
Other
10%
United States Renal Data System. Annual data report. 2000.
No. of patientsProjection95% CI
1984 1988 1992 1996 2000 2004 20080
100
200
300
400
500
600
700
r2=99.8%243,524
281,355520,240
No
. o
f d
ialy
sis
pat
ien
ts
(th
ou
san
ds)
©2006. American College of Physicians. All Rights Reserved.
Cardiovascular Comorbidities, 5% Medicare sample, by Diabetes and CKD status, 1999-2000
Non-diabetes Diabetes
Non-CKD
CKD
0
15
30
45
60
Non-diabetes Diabetes
Non-CKD
CKD
0
15
30
45
60
Non-diabetes Diabetes
Non-CKD
CKD
0
15
30
45
60
Non-diabetes Diabetes
Non-CKD
CKD
0
15
30
45
60
%Stroke/TIA
%ASHD %Amputation/PVD
%Heart Failure
©2006. American College of Physicians. All Rights Reserved.
Level of Kidney Function Is an Level of Kidney Function Is an Independent Risk Factor For CV RiskIndependent Risk Factor For CV Risk
N=15,350Mean follow-up=6.2 yearsAge -45-64
Stage of Kidney Disease NStage of Kidney Disease N
Stage 2 (GFR-60-89) 7,665
Stage 3 &4 (GFR-15-59) 444
1.0 1.25 1.751.5 2.0
1.38
1.16
Manjunath G et.al JACC 2003;41:47-55
0.75
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Go, A. S. et al. N Engl J Med 2004;351:1296-1305
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CKD Hospitalization Rates for Cardiovascular DiseaseCKD Hospitalization Rates for Cardiovascular Disease
• CHF admission rates are 5 times higher in CHF admission rates are 5 times higher in patients with a diagnosis of CKD vs non-patients with a diagnosis of CKD vs non-CKDCKD
• Ischemic heart disease admissions at 2-2.5 Ischemic heart disease admissions at 2-2.5 times higher in the CKD populationtimes higher in the CKD population
• Cardiac arrhythmia admission rates are Cardiac arrhythmia admission rates are twice as common in CKD populationstwice as common in CKD populations
©2006. American College of Physicians. All Rights Reserved.
US
RD
S
CKD Prevalence in US (AJKD 2002)CKD Prevalence in US (AJKD 2002)
300,000 400,000
7,600,000
5,300,0005,900,000
0
1,000,000
2,000,000
3,000,000
4,000,000
5,000,000
6,000,000
7,000,000
8,000,000
Stage 5 Stage 4 Stage 3 Stage 2 Stage 1
GFR (ml/min) <15 15-29 30-59 60-89 > 90
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CVD Risk FactorsCVD Risk Factors Hypertension* Cigarette smoking Obesity* (BMI >30 kg/m2) Physical inactivity Dyslipidemia* Diabetes mellitus* Microalbuminuria Estimated GFR <60 ml/min Age (older than 55 for men, 65 for women) Family history of premature CVD
(men under age 55 or women under age 65)*Components of the metabolic syndrome. Chobanian A et.al Hypertension, Dec. 2003
©2006. American College of Physicians. All Rights Reserved.
0
100
200
300
400
500
600
700
800
900
1000
Microalbuminuria Albuminuria (Proteinuria)
mg/
day
CV Risk and Vascular Dysfunction
CV Risk and Presence of RenalDysfunction and Vascular Dysfunction
Normal
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Proteinuria Predicts Stroke and Proteinuria Predicts Stroke and CHD Events in Type 2 DiabetesCHD Events in Type 2 Diabetes
P<0.001
40
30
20
10
0Stroke CHD
Events80604020
0
0.5
0.6
0.7
0.8
0.9
1
Su
rviv
al C
urv
es F
or
CV
Mo
rtal
ity
Overall: P<0.001C
B
A
Inci
den
ce(%
)
Months
Miettinen H et al. Stroke. 1996;27:2033-2039.
B: U-Prot 150–300 mg/LA: U-Prot <150 mg/L C: U-Prot >300 mg/L
0
U-Prot = Urinary protein concentration.
100
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Berton G et.al. Diabetologia, Aug. 2004
Kaplan-Meier curves of 3-year all-cause mortality in the AMI patients stratifiedby DM status and ACR >30µg/mg or <30µg/mg on the 3rd day after admission
©2006. American College of Physicians. All Rights Reserved.
0 0.5 1 1.5 2 3 4 5
Mortality
Hazard Ratio ( 95% CI ) for Values Above 80th Percentile
Use of MAU, CRP, and BNP as Predictors of Mortality and CV Events
NT-proBNP
CRP
MAU
First Major CV Event
NT-proBNP
CRP
MAU
P=.007
P=014
P=.008
P=.003
P=.96
P=<.001
Adjusted for age, sex, smoking, DM, HTN, Afib, LVEF<50%, LVH, total cholesterol, serum creatinine. Mortality analysis based on 91 deaths, and CV event data based on 63 events due to missing covariates. The 80 th percentile corresponds to values more than 5.85 pg/mL for NT-proBNP, 5.76 mg/L for CRP, and 18.4 mg/g for MAU.
Kistorp K, et al. JAMA. 2005;293:1609-1616.
©2006. American College of Physicians. All Rights Reserved.
0
-5
5
10
15
-100 -50 0 50 100
Rat
e o
f d
eclin
e in
GF
R
(ml/
min
/ ye
ar)
r = 0.47
p < 0.011
delta Proteinuria (% change from pretreatment)
Predictive value of antiproteinuric effect on renal protection
Apperloo AJ et al; Kidney Int 1994; 45:S174-8.Rossing P et al. Diabetologia. 1994;37:511-516.
15
10
5
0
-5
-100 -50 0 50 100
r=0.73p<.001.
Diabetes Non-Diabetes
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Clinical Trials and Renal Outcomes Clinical Trials and Renal Outcomes Based on Proteinuria ReductionBased on Proteinuria Reduction
Clinical Trials and Renal Outcomes Clinical Trials and Renal Outcomes Based on Proteinuria ReductionBased on Proteinuria Reduction
Increased Time to DialysisIncreased Time to Dialysis(30-35% proteinuria reduction)(30-35% proteinuria reduction)
Captopril TrialCaptopril Trial--N Engl J Med, 1993N Engl J Med, 1993
AASK AASK Trial-Trial-JAMA, 2001JAMA, 2001
RENAALRENAAL--N Engl J Med, 2001N Engl J Med, 2001
IDNTIDNT--N Engl J Med, 2001N Engl J Med, 2001
COOPERATECOOPERATE-Lancet, 2003-Lancet, 2003
No Change in Time to DialysisNo Change in Time to Dialysis
(NO proteinuria reduction)(NO proteinuria reduction)
DHPCCB arm-DHPCCB arm-IDNTIDNT
DHPCCB arm-DHPCCB arm-AASKAASK
Hart P & Bakris GL Managing Hypertension in the Diabetic Patient. IN: Egan BM, Basile JN, and Lackland DT (eds.) Hot Topics in Hypertension Hanley and Belfus, Philadelphia, 2004, pp.249-252.
©2006. American College of Physicians. All Rights Reserved.
IDNT Proportion of Patients with the Primary IDNT Proportion of Patients with the Primary Composite Endpoint*Composite Endpoint*
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Pro
port
ion
wit
hp
rim
ary
en
dp
oin
t
0 6 12 18 24 30 36 42 48 54
579 555 528 496 400 304 216 146 65
565 542 508 474 385 287 187 128 46
568 551 512 471 401 280 190 122 53
Irbesartan (n)
Amlodipine (n)
Placebo (n)
Months of Follow-up
*Composite of a doubling of serum creatinine, end stage renal disease, or death
P=0.02 for irbesartan compared to placebo
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.©2001 Massachusetts Medical Society. All rights reserved.
©2006. American College of Physicians. All Rights Reserved.
Relationship Between Rate of Decline in Renal Relationship Between Rate of Decline in Renal Function and Change in Proteinuria in IDNTFunction and Change in Proteinuria in IDNT
Lewis EJ et al. N Engl J Med. 2001;345:851-860.
Amlodipine
Irbesartan Placebo
Creatinine clearance (mL/min/1.73 m2)
Proteinuria (g/d)
-8
-7
-6
-5
-4
-3
-2
-1
0
©2006. American College of Physicians. All Rights Reserved.
RENAAL; Baseline Proteinuria as a Determinant for Cardiac Events in Type 2 diabetes
CV Endpoint Heart Failure
0
2
4
6
Haz
ard
ratio
5.25
Albuminuria (g/g)
0
2
4
6
<.5 2.0 2.95 4.4 5.25
Albuminuria (g/g)
<.5 2.0 2.95 4.4
Haz
ard
ratio
De Zeeuw et al; Circulation 2004
(adjusted for all conventional risk factors)
©2006. American College of Physicians. All Rights Reserved.
RENAAL; Baseline Proteinuria as a Determinant for RENAL Events in Type 2 Diabetes
De Zeeuw et al; Kidney Int 2004
Primary composite Endpoint
0
10
15
5
Haz
ard
ratio
<.5 2.0 2.95 4.4 5.25
Baseline Albuminuria (g/g) Baseline Albuminuria (g/g)
0
<.5 2.0 2.95 4.4 5.25
ESRD
10
20
30
H
azar
d ra
tio
(adjusted for all conventional risk factors)
©2006. American College of Physicians. All Rights Reserved.
De Zeeuw D, et al. Kidney Int. 2004; 65:2309.
6060
5050
4040
3030
2020
1010
00
% w
ith E
RS
D%
with
ER
SD
00 1212 2424 3636 4848
MonthMonth
6060
5050
4040
3030
2020
1010
00
% w
ith r
en
al e
nd
po
int
% w
ith r
en
al e
nd
po
int
00 1212 2424 3636 4848
MonthMonth
<0%<0%
0<30%0<30%
30%30%
<0%<0%
0<30%0<30%
30%30%
Δ Alb: Δ Alb: 0<30 vs. <0%0<30 vs. <0%Δ Alb: Δ Alb: 30 vs. <0%30 vs. <0%Δ Alb: Δ Alb: 30 vs. 30 vs. 0<30%0<30%
0.880.880.600.600.680.68
0.15700.1570<.0001<.00010.00030.0003
HRHR PP values values
UnadjustedUnadjusted
Renal End PointRenal End Point
0.760.760.460.460.610.61
0.00280.0028<.0001<.0001
<.0001 <.0001
HRHR PP values values
AdjustedAdjusted
Δ Alb: Δ Alb: 0<30 vs. <0%0<30 vs. <0%Δ Alb: Δ Alb: 30 vs. <0%30 vs. <0%Δ Alb: Δ Alb: 30 vs. 30 vs. 0<30%0<30%
0.820.820.510.510.620.62
0.12420.1242<.0001<.00010.00190.0019
HRHR PP values values
UnadjustedUnadjusted
Renal End PointRenal End Point
0.620.620.370.370.600.60
0.00030.0003<.0001<.0001
<.0010 <.0010
HRHR PP values values
AdjustedAdjusted
RENAAL: Renal End Points By RENAAL: Renal End Points By 6-Month Changes in Albuminuria6-Month Changes in Albuminuria
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De Zeeuw D, et al. Circulation. 2004;110:921.
4040
% w
ith C
V e
nd
po
ints
% w
ith C
V e
nd
po
ints 3030
2020
1010
0000 1212 2424 3636 4848
MonthMonth
CV EndpointCV Endpoint4040
% w
ith C
V e
nd
po
ints
% w
ith C
V e
nd
po
ints 3030
2020
1010
0000 1212 2424 3636 4848
MonthMonth
Heart FailureHeart Failure
<0%<0%
>30%>30%
<0%<0%
>30%>30%
RENAAL: Cardiovascular End Points RENAAL: Cardiovascular End Points by 6-Month Changes in Albuminuriaby 6-Month Changes in Albuminuria
©2006. American College of Physicians. All Rights Reserved.
Most Common Cause of Failing to Reduce Proteinuria with ACE Inhibitor or ARB
High SALT intake (>5 grams/day)
DeZeeuw D et.al Kidney Int., 1989, Mishra SI et.al, Curr Hypertens Rep, 2005
©2006. American College of Physicians. All Rights Reserved.
What is the Goal BP and Initial Therapy in Kidney Disease or Diabetes to Reduce CV Risk?
Group Goal BP (mmHg) Initial Therapy
Am. Diabetes Assoc (2006) <130/80 ACE Inhibitor or ARB* KDOQI (NKF) (2004) <130/80 ACE Inhibitor or ARB* JNC 7 (2003) <130/80 ACE Inhibitor or ARB* Canadian HTN Soc. (2002) <130/80 ACE Inhibitor or ARB Am. Diabetes Assoc (2002) <130/80 ACE Inhibitor or ARB Natl. Kidney Fdn.-CKD(2002) <130/80 ACE Inhibitor or ARB* Natl. Kidney Fdn. (2000) <130/80 ACE Inhibitor* British HTN Soc. (1999) <140/80 ACE Inhibitor WHO/ISH (1999) <130/85 ACE Inhibitor JNC VI (1997) <130/85 ACE Inhibitor
* Indicates use with diuretic
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DETAIL, a prospective, multicenter, non-inferiority trial randomized 250 patients with type 2 diabetes, hypertension (BP <180/95 mm Hg), and evidence of early nephropathy (GFR >70 mL/min/1.73 m2) to either telmisartan or enalapril.
Followed for 5 years
Barnett AH et.al N Engl J Med 2004;351:1952-1961.
Angiotensin-Receptor Blockade versus Converting–Enzyme Inhibition in Type 2 Diabetes and Nephropathy
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Barnett AH et.al N Engl J Med 2004;351:1952-1961.
Angiotensin-Receptor Blockade versus Converting–Enzyme Inhibition in Type 2 Diabetes and Nephropathy-RESULTS
Baseline GFR 91 ml/min
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Effects of ACE Inhibitors or ARBs on Renal Disease Progression: A Meta-Analysis Cases J et.al. Lancet 2005;366:2026
ESRD
2X SCr
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Effects of ACE Inhibitors or ARBs on Renal Disease Progression: A Meta-Analysis Cases J et.al. Lancet 2005;366:2026
ESRD
2X SCr
©2006. American College of Physicians. All Rights Reserved.
-9.4
-1.3
-4
-7
-10
-8
-6
-4
-2
0
mL
/min
/yr.
mm
Hg
Initial GFR Rateof Decline
[<4 Months] 130130
140140
150150
Systolic PressureTrial End
Bakris(N = 18)
Nielsen(N = 21)
Final GFR Rateof Decline
[Trial End (1–6 years)]
136
154
Bakris GL & Weir M Arch Intern Med. 2000:160:685-693
Effect Of Early And Late Changes In GFR When Blood Pressure Is Controlled with an ACE Inhibitor
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Tarif N and Bakris GL. IN: Johnson R and Freehally J (eds.) Principles of Nephrology Mosby & Co. London, 2000 pp. 40.1-12, Ashgar A & Bakris, G Primer in Kidney Disease, 2005
Most Likely Etiologies for Increasing Serum Creatinine
Volume Depletion
Heart Failure Bilateral Renal Artery Stenosis
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General Concept
A rise in serum creatinine of up to 30% of baseline ( given baseline up to 3 mg/dl) that remains stable in the absence of hyperkalemia ([K+] > 6) correlates with slower renal disease progression.
Bakris GL & Weir M Arch Intern Med. 2000:160:685-693
©2006. American College of Physicians. All Rights Reserved.
Intensive Multiple Risk Factor ManagementIntensive Multiple Risk Factor Management
Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%).*Death from CV causes, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention,
nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease.†Behavior modification and pharmacologic therapy.
Pri
mar
y C
om
po
site
En
d P
oin
t* (
%)
Months of Follow-up
60
40
20
12 24 36 48 60 72 84 96
Conventional Therapy
Intensive Therapy†
20% Absolute Risk Reduction
N=160; follow-up = 7.8 years
Patients with Type 2 Diabetes and Microalbuminuria
Aggressive treatment of†:– Microalbuminuria with ACEIs, ARBs, or combination– Hypertension– Hyperglycemia– Dyslipidemia– Secondary prevention of CVD
Adapted from Gæde P et al. N Eng J Med. 2003;348:383-393
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Saydah S et.al JAMA 2004;291:335
Percentage of Adults with Diabetes Who Achieved Recommended Goals of Cardiovascular Risk Factors in
NHANES
0
10
20
30
40
50
HbA1c<7% BP <130/80mmHg
TC <200mg/dl
GoodControl
NHANES III NHANES IV
%
©2006. American College of Physicians. All Rights Reserved.
(if systolic BP >20 mmHg above goal)START with ACEI or ARB/thiazide diuretic*)
If BP Still Not at Goal (130/80 mm Hg)
If BP Still Not at Goal (130/80 mm Hg)
orIf used CCB, Add Other Subgroup of CCB
(ie, amlodipine-like agent if verapamil or diltiazem already being used and the converse)
OR if blocker used add CCB
Add Vasodilator (hydralazine, minoxidil) ORRefer to a Clinical Hypertension Specialist
If BP Still Not at Goal (130/80 mm Hg)
Add Long Acting Thiazide Diuretic*
If Blood Pressure >130/80 mm Hg in Diabetes or Chronic Kidney Disease with Any Level of Albuminuria
Recheck within 2-3 weeks
Recheck within 2-3 weeks
Recheck within 4 weeks
(if systolic BP< 20 mmHg above goal)Start ARB or ACE Inhibitor titrate upwards
Add CCB or blocker** (titrate dose upward)
Ashgar and Bakris, Primer of Kidney Diseases, 2005
Consider low dose aldosterone antagonists#
©2006. American College of Physicians. All Rights Reserved.
Messages to Take Home
Kidney Disease is a silent killer-(no signs or symptoms until you loose >70% of your kidney function,
The risk of dying from a cardiovascular event, if you’ve lost 50% or more of your kidney function, is similar to that having had a heart attack.
Proteinuria reduction needs to be a key part of blood pressure management.
©2006. American College of Physicians. All Rights Reserved.