Hypertension and Diabetic Kidney Disease Progression Hypertension and Diabetic Kidney Disease Progression

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


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%


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


Walking the dog


Incidence of Kidney Failureper million population, 1990, by HSA, unadjusted





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)


Cardiovascular Comorbidities, 5% Medicare sample, by Diabetes and CKD status, 1999-2000

Non-diabetes Diabetes

Non-CKD

CKD

0

15

30

45

60


Non-CKD

CKD

0

15

30

45

60


Non-CKD

CKD

0

15

30

45

60


Non-CKD

CKD

0

15

30

45

60

%Stroke/TIA

%ASHD %Amputation/PVD

%Heart Failure


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


Go, A. S. et al. N Engl J Med 2004;351:1296-1305


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


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


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


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


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


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


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.


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


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.


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.


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


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)


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)


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


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


UnadjustedUnadjusted

Renal End PointRenal End Point

0.620.620.370.370.600.60

0.00030.0003<.0001<.0001

<.0010 <.0010


AdjustedAdjusted

RENAAL: Renal End Points By RENAAL: Renal End Points By 6-Month Changes in Albuminuria6-Month Changes in Albuminuria


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


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


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


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


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


Effects of ACE Inhibitors or ARBs on Renal Disease Progression: A Meta-Analysis Cases J et.al. Lancet 2005;366:2026

ESRD

2X SCr


Effects of ACE Inhibitors or ARBs on Renal Disease Progression: A Meta-Analysis Cases J et.al. Lancet 2005;366:2026

ESRD

2X SCr


-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


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


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


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


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

%


(if systolic BP >20 mmHg above goal)START with ACEI or ARB/thiazide diuretic*)

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


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#


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.


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Hypertension and Diabetic Kidney Disease Progression Hypertension and Diabetic Kidney Disease Progression