Hypertensive Renal Disease in African-Americans

Janice P. Lea, MD, MSc

Associate Professor of Medicine

Clinical Specialist in Hypertension

Renal Division, Emory University

Diabetes and Hypertension: The Leading Causes 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 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 20100

100

200

300

400

500

600

700

R2 = 99.8%

243,524

281,355520,240

Number of Dialysis Patients

Stage 5 CKD Incidence Rates per Million Vary by Race/Ethnicity

254†

471*395*

696*

988*

325†

0

250

500

750

1000

Caucasian Black NativeAmerican

Asian Non-Hispanic

Hispanic

Odds ratios: 1 3.89 2.74 1.56 1 1.45

*P<0.0001†Reference population.Data adjusted for age and gender from 2001 in United States Renal Data System.2003 Annual Data Report. Available at: www.usrds.org.

Inci

den

ce R

ate

per

Mil

lio

n

(200

1)

NHANES III: Adjusted Odds of Reduced Kidney Function

0.370.56

1.1

1.00Referent

0.00

1.00

2.00

AdjustedOdds Ratio

Coresh et al. Am J Kidney Dis. 41:1-12, 2003

GFR >90 60-89 30-59 15-29

AA (%) 79.2 17.4 3.1 0.25

White (%) 59.7 35.2 4.8 0.21

Increasing Numbers of Patients May Overwhelm Nephrologists (amjkd,coresh 2003,nni 1999)

Stage Description eGFR PrevalencePatients per Nephrologist

1Kidney damage with normal or increased GFR

90 5,900,000 1180

2Mild decrease in GFR 60-89 5,300,000 1060

3Moderate decrease in GFR 30-59 7,600,000 1520

4Severe decrease in GFR 15-29 400,000 80

5 Kidney failure<15 or dialysis

350,000 70

Five-Year Outcomes of CKD

Stage of CKD

Patients on RRT (%)

Patient Deaths (%)

2 1.1 19.5

3 1.3 24.3

4 19.9 45.5

RRT = renal replacement therapy.Keith et al. Arch Intern Med. 2004;164:659-663.

Cardiovascular Disease (CVD) Is Linked to Chronic Kidney Disease (CKD)

Relative Risk of CVD is 1.4 – 2.05 X with

Creatinine > 1.4 – 1.5 mg/dl

Relative Risk of CVD is 1.5 – 3.5 X with

Microalbuminuria

Annual Mortality from CVD is 10 to 100-Fold Greater

with Kidney Failure Flack, et al.

1993

Levey, et al.

1998

Jensen, et al.

2000

Ruilope, et al.

2001

Mann, et al.

2001

Rates of Death and Cardiovascular Events in Patients According to GFR

N = 1,120,295 adults. *Age-standardized rates per 100 person-years; †Cardiovascular event defined as hospitalization for coronary heart disease, heart failure, ischemic stroke, and peripheral arterial disease per 100 person-years. Go et al. N Engl J Med. 2004;351:1296-1305.

14.14

0.76 1.08

4.76

11.36

0

2

4

6

8

10

12

14

≥60 45-59 30-44 15-29 <15

Ra

te o

f D

ea

th F

rom

An

y C

au

se

* 36.60

2.113.65

11.29

21.80

0

5

10

15

20

25

30

35

40

≥60 45-59 30-44 15-29 <15 R

ate

of

CV

Ev

en

ts†

eGFR (mL/min/1.73 m2)

The Dual Significance of Proteinuria

• Proteinuria (albuminuria) results from injury to glomerular circulation Increased proteinuria (albuminuria) is associated

with progressive kidney disease

• In diabetes and hypertension, proteinuria (albuminuria) is also an indicator of injury in the systemic circulation Proteinuria (albuminuria) is associated with

increased cardiovascular risk

Proteinuria Is a Risk Factor for CVD

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Composite End-point

CV mortality All-causemortality

Stroke MI

I II

Primary composite end-point: CV death, stroke, MI. Primary composite end-point: CV death, stroke, MI. Wachtell et al. Wachtell et al. Ann Intern MedAnn Intern Med. 2003;139:901-906.. 2003;139:901-906.

Comparison of lowest and highest decile of Comparison of lowest and highest decile of microalbuminuria in 7143 nondiabetic patientsmicroalbuminuria in 7143 nondiabetic patients

Ad

just

ed

Ha

zard

Rat

ioA

dju

ste

d H

aza

rd R

atio

Microalbuminuria Predicts CV Risk at Levels Below Current Definition

Wachtell K et al. Ann Intern Med. 2003;139:901-906.

Microalbuminuria assessment in patients with hypertension and diabetes improves CV risk stratification

Quintile of urine A/C ratio (mg/g) among 1,063 hypertension patients with diabetes

10

Normoalbuminuria Microalbuminuria

Ad

just

ed H

azar

d R

atio

0

0.5

1

1.5

2

2.5

<6.9 6.9 – <17.2

149.4

LIFE Study: Composite Endpoint

17.2 – <45.0

45.0 – <149.4

Proteinuria Is Also a Risk Factor for Progression of CKD

% W

ith

Do

ub

ling

%

Wit

h D

ou

blin

g

of

SC

r o

r E

SR

Do

f S

Cr

or

ES

RD

**PP-values are for comparison across the subgroups.-values are for comparison across the subgroups.Jafar et al. Jafar et al. Kidney Int.Kidney Int. 2001;60:1131-1140. 2001;60:1131-1140.

Urine Protein (g/d)Urine Protein (g/d)

PP<.001*<.001*

00

1010

2020

3030

4040

5050

<0.5<0.5 0.5-3.00.5-3.0 3.0-6.03.0-6.0 >6.0>6.0

Early Treatment Makes a Difference

Primary end point: doubling of SCr or kidney failure.Nakao et al. Lancet. 2003;361:117-124.

ACE Inhibitors, ARBs, and Combination Therapy in Nondiabetic Nephropathy

0

5

10

15

20

25

30

0 6 12 18 24 30 36Follow-Up (mo)

Pat

ien

ts R

each

ing

En

d P

oin

t (%

)

*

P = 0.02

Combination* (n = 88)

Losartan (n = 89)

Trandolapril (n = 86)

Features of Hypertensive Nephrosclerosis

• Long history of HTN, prior to known kidney dz.• No other etiology for kidney disease.• Proteinuria < 2.5 g/d. Urinalysis no cells. No

Diabetes.• Evidence of other target organ damage-LVH,eye• FH of HTN, high risk in African-Americans, age of

onset of HTN- 25-45.• Renal biopsy- hyalinization arterioles, intimal thick.

small arteries, glom ischemia, fibrosis tubules

Treatment of Hypertension in Nondiabetic Kidney Disease

http://www.kidney.org/professionals/kdoqi/guidelines_bp

-1.7-3

-2.3

-6.1-7.3

-6.4-5.8

-14.2

-16.7-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Week 4 Week 8 Week 12

PlaceboLosartanLos/HCTZ

*P0.01 vs placebo. † P0.05 vs placebo.

Clin. Therapeutics, 2001

† **

*

*

*

African Americans: Addition of a Diuretic

to ARB Therapy (N=440) C

han

ge in

sys

toli

c B

P (

mm

Hg)

Average Number of Antihypertensive Agents Needed Per Patient to Achieve

Diastolic BP Goals

Bakris et al. Am J Kidney Dis. 2000;36:646.

1 1.5 2 2.5 3 3.5 4

AASK (<92 mm Hg MAP)

HOT (<80 mm Hg Diastolic)

MDRD (<92 mm Hg MAP)

ABCD (<75 mm Hg Diastolic)

UKPDS (<85 mm Hg Diastolic)

No. of BP medications

African American Study of Kidney Disease and Hypertension (AASK)

Therapy: Usual Aggressive

Goal MAP: 102-107 mm Hg 92 mm Hg

N = 217 Amlodipine Amlodipine

N = 436 Ramipril Ramipril

N = 441 Metoprolol Metoprolol

• 1094 patients with HTN and CKD , 4 yr f/uGFR = 20-65 mL/min/1.73 m2

• Excluded DBP <95 mm Hg, DM, UP/Cr >2.5

MAP = mean arterial pressure; DBP = diastolic blood pressure; UP/Cr = urinary protein to creatinine ratio.Wright et al for the AASK Study Group. JAMA. 2002;288:2421-2431.

AASK Study Questions

• Does very aggressive lowering of blood pressure result in slower decline in renal function in hypertensive renal disease?

• Does the type of antihypertensive agent used to initiate blood pressure lowering matter with regard to renal outcomes?

Baseline Characteristics (2)

0.63 1.110.44 0.72

31.8

0.57 0.990.38 0.73

32.7

0.61 1.010.41 .75

33.0

Urine Protein (g/d) Male Female% with UP/Cr > 0.22

2.14 0.751.80 0.55

2.28 0.831.74 0.55

2.18 0.741.76 0.59

Serum Creatinine (mg/dL)

Male Female

MetoprololN=441

AmlodipineN=217

RamiprilN=436

Mean SD or %. No significant differences among drug groups.

Clinical Evidence for Risk Reduction With

ACE Inhibitor or Blockade: AASK

-50

-40

-30

-20

-10

0

Co

mp

osit

e R

isk (

%)

Patients with existing kidney damage (baseline UP/Cr >0.22).Wright et al for the AASK Study Group. JAMA. 2002;288:2421-2431.

Ramipril vs Amlodipine

P = 0.004

Ramipril vs Metoprolol

P = 0.04

Metoprolol vs Amlodipine

P = 0.17

-38

-22 -20

Composite risk of rapid GFR decline-decrease from baseline of 50% or 25 mL/min/1.73 m2, kidney failure, or death

Percent Change in Proteinuria from Baseline

Geometric mean urine protein/creatinine ratio declined faster in ramipril and metoprolol groups than amlodipine group (p < 0.001)

% C

han

ge

(SE

)

-33

-18

0

22

49

82

122

172

Follow-up Month0 6 12 18 24 30 36 42 48

Metoprolol

RamiprilAmlodipine

% of Patients Reached Urine Protein/Creatinine Ratio>0.22During Follow-up by Drug Group

Ramipril vs. Metoprolol: p=0.014Amlodipine vs. Metoprolol: p=0.009

Ramipril vs. Amlodipine: p<0.001

% w

ith

Eve

nts

0

10

20

30

40

50

60

Follow-up Month0 6 12 18 24 30 36 42 48 54 60

Analysis of patients with UP/Cr < 0.22 at baseline

MetoprololRamiprilAmlodipine

African American Study of Kidney Disease and Hypertension (AASK) Trial

Wright et al. JAMA. 2002;288:2421-2431.

Amlodipine Treatment Arm

Proteinuric patients progressed more rapidly

to a renal event

In patients with baseline urinary protein/creatinine ratio >0.22 (≈ baseline protein >300 mg/d)

Ramipril Treatment Arm Metoprolol Treatment Arm

The AASK trial, like other studies, confirms that amlodipine is associated

with increases in proteinuria

Role of Angiotensin II in Renal Disease Pathways

Ang II

Efferentconstriction

PG, NO

Afferentdilation

Glomerular hypertension

Proteinuria

Focal segmental glomerulosclerosis

Hypertension

TGF-

Extracellular matrixInterstitial fibrosis

PG = prostaglandin; NO = nitric oxide.

METHODS

• Post hoc analysis of a randomized 3X2 factorial trial (AASK).

• Outcomes: 1) GFR slope – analyzed by single-slope mixed effects model 2) ESRD- Cox proportional hazards regression analysis

• Predictor variables: 1) baseline proteinuria 2) baseline GFR 3) initial change in proteinuria at 6 months

Lea J et.al. Arch Intern Med. 2005;165:947

Six Month Change in Proteinuria from Baseline Predicts Outcome of Kidney Disease: Results

from the AASK trial 4.0

2.0

1.0

0.5

0.25

>-50%

0.125

>-50% to 20%

-20% to +25%

+25% to 100%

>+100%

Relative Risk of ESRD

Conclusions

• Changes in low levels of proteinuria (microalbuminuria) are predictive of ESRD in nondiabetic kidney disease.

• The association of early changes in proteinuria with subsequent renal outcomes suggests that effects of antihypertensive agents on proteinuria should be considered when selecting agents for their potential to slow renal disease progression.

Metabolic Syndrome and CKD

• The metabolic syndrome is independently associated with an increased risk for incident CKD in nondiabetic adults in a prospective study – ARIC (Chertow et al, JASN 2005).

• Metabolic syndrome is a strong and independent risk factor for chronic kidney disease in a cross-sectional analyses of 6217 subjects from NHANES. The multivariate adjusted OR of CKD in subjects with MS was 2.6 compared to those without MS (Chen et al, Ann. Intern. Med. 2004).

OBJECTIVE

• Does Metabolic Syndrome predict the rate of CKD progression to ESRD in African-Americans with Hypertensive Renal Disease??

African American Study of Kidney Disease and Hypertension (AASK)

Therapy: Usual Aggressive

Goal MAP: 102-107 mm Hg 92 mm Hg

N = 217 Amlodipine Amlodipine

N = 436 Ramipril Ramipril

N = 441 Metoprolol Metoprolol• 1094 patients with HTN and CKD , 4 yr f/u

GFR = 20-65 mL/min/1.73 m2

• Excluded DBP <95 mm Hg, DM or FBS>140, UP/Cr >2.5

MAP = mean arterial pressure; DBP = diastolic blood pressure; UP/Cr = urinary protein to creatinine ratio.Wright et al for the AASK Study Group. JAMA. 2002;288:2421-2431.

METHODS

• Predictor variables: individual and composite components of the metabolic syndrome at baseline defined by the presence of any two of the following in addition to hypertension (NCEP):– fasting plasma glucose>110 mg/dl

– triglycerides> 150 mg/dl

– HDL chol <40 mg/dl in men, < 50 mg/dl in women

– BMI>30.

– Note: BP >130/85 or on meds was present in all.

ATP III: The Metabolic Syndrome*

*Diagnosis is established when 3 of these risk factors are present

Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

< 40 mg/dL< 50 mg/dL< 40 mg/dL< 50 mg/dL

MenWomenMenWomen

> 102 cm (> 40 in)> 88 cm (> 35 in)> 102 cm (> 40 in)> 88 cm (> 35 in)

MenWomenMenWomen

110 mg/dL 110 mg/dLFasting glucoseFasting glucose

130/ 85 mm Hg 130/ 85 mm HgBlood pressureBlood pressure

HDL-CHDL-C

150 mg/dL 150 mg/dLTGTG

Abdominal obesity† (Waist circumference‡)Abdominal obesity† (Waist circumference‡)

Defining LevelDefining LevelRisk FactorRisk Factor

METHODS

• Outcome: Time until the clinical composite outcome including: 50% or 25 ml/min/1.73m2 GFR decline (GFR event)-iothalamate, ESRD, or Death.

• Statistical Analyses: Multivariable Cox Proportional Hazards Models run for the metabolic syndrome composite and for each covariate with the composite renal outcome with and without adjustments for covariates.

RESULTS

• 41% met criteria for metabolic syndrome using modified NCEP.

• 40.6% had BMI > 30 kg/m2 .

• None of the individual components of the MS predicted CKD progression in multivariate tests.

Baseline CharacteristicsVariable Total

(n=1094) (SD)

MS + (n=208)

MS –(n=634)

P value

BMI 30.6(6.5) 33.5(6.2) 28.6(6.1) <.0001

gluc 94.9(18.5) 105.2(21.5) 91.4(15.7) <.0001

HDL 48.3(16.1) 40(12.2) 54(15.6) <.0001

TRIG (n=842)

140.5(81) 186(95.6) 107(48.4) <.0001

SBP 150(23.8) 148(23.3) 151(24) .15

DBP 95.5(14) 95.6(14.3) 95(24) .65

Cox Regression Analyses with Renal Outcomes

Met. Syndrome

componentsMultivariate HR(CI)

P value

BMI>30 1.0(.78-1.3) .95

Glucose>110 1.14(.77-1.7) .51

HDL<40 .95(.73-1.23) .67

TRIG>150 1.25(.96-1.62) .09

SBP>140 1.1(.83-1.5) .48

DBP>90 1.2(.87-1.62) .28

Modified NCEP with BMI

• 41% subjects meet criteria for metabolic syndrome.

• Cox model – unadjusted HR- 1.31 (1.02-1.67), p=.03 for MS with composite outcomes.

• Adjusted for all covariates except proteinuria- HR-1.37(1.06-1.77), p=.013. With proteinuria- 1.23 (.95-1.58), p=.11.

TABLE 3: Hazard ratio of metabolic syndrome with Time to Event analyses with and without adjustments for significant covariates and BMI and adjusted for BP goal group and Antihypertensive Drug group.

    Hazard Ratio Confidence Interval P value

MS unadjusted 

1.31 1.03-1.68 .03

MS adjusted for other covariates,+ uprot/cr

1.37

1.23

1.07-1.77

.95-1.58

.01

.11

By BP goal 1.37 1.05-1.8 .02

By Drug group 1.35 1.03-1.78 .03

Cox regression analyses for ESRD alone, ESRD + death

• MS and ESRD alone, HR- 1.73( 1.2-2.5).

• MS and ESRD+death, HR- 1.62 (1.2-2.2).

Cox Model for Metabolic Syndrome and Renal Outcomes

Variable HR CI

MS 1.23 .95-1.58

Age 1.01 .78-1.31

Males .89 .72-1.2

smoker 1.49 1.15-1.95

alcohol 1.11 .84-1.46

BUN 1.0 .72-1.39

Cr 1.78 1.3-2.8

GFR .61 .37-.67

Phos 1.24 .98-1.65

Uric acid .89 .68-1.17

UProt/Cr 2.76 2.1-3.6

Cox Model for Metabolic Syndrome and Renal Outcomes

Variable HR CI

MS 1.37 1.07-1.77

Age 1.01 .78-1.31

Males .94 .72-1.2

smoker 1.49 1.15-1.95

alcohol 1.11 .84-1.46

BUN 1.0 .72-1.39

Cr 1.96 1.3-2.8

GFR .51 .37-.67

Phos 1.27 .98-1.65

Uric acid .89 .68-1.17

Kaplan Meier Survival Curve – Metabolic Syndrome status

0. 00

0. 25

0. 50

0. 75

1. 00

Mos t o dt h, di al , gevnt , ADM

0 10 20 30 40 50 60 70 80

STRATA: MS=1 Censor ed MS=1MS=2 Censor ed MS=2

Strengths and Limitations

• Well-characterized population of African-Americans with CKD.

• Iothalamate GFR’s to assess renal function.

• No waist circumferences, but BMI used to assess obesity.

• 242 missing values- lack of triglycerides.

SUMMARY

– African-Americans with CKD in the AASK Study have a prevalence of metabolic syndrome (NCEP) of 41%.

– African-Americans with hypertensive CKD and metabolic syndrome have a 37% higher risk of reaching the composite clinical endpoints of GFR decline, ESRD, or death.

– These findings persisted after adjusting for other factors known to influence renal outcomes except for proteinuria and did include adjustments for BP goal group and antihypertensive therapy.

Conclusions

– This is the first prospective study reporting that metabolic syndrome predicts the rate of CKD progression.

– Further studies are needed to confirm this association and should include more specific measures of insulin resistance.

– Our findings may explain some of the variability observed in the progression to ESRD and may provide a new target for treating CKD in a high risk group.

You Have The Power To

Prevent Kidney Disease

0

10

20

30

40

50

60

70

80

90

Proportion of MDs responding

AA Race DM HBP FH

Risk Factor

Does not

Slightly

Moderately

Greatly

Perception of increased risk of CKD by patient characteristic as reported by primary

care physicians

Reducing Risks of Kidney Disease in African-Americans

• Education• Early detection of kidney disease• Adequate treatment of hypertension and diabetes• Adequate access to healthcare• Proper dietary habits• More clinical research in African-Americans to

better understand the increased risks