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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
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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