Hypertensive Renal Disease in AfricanAmericans

1
Hypertensive Renal Disease in African-Americans

• Janice P. Lea, MD, MSc
• Associate Professor of Medicine
• Clinical Specialist in Hypertension
• Renal Division, Emory University

2
Diabetes and Hypertension The Leading Causes of
ESRD
Primary Diagnosis For Patients Who Start Dialysis
700
600
500
Number of Dialysis Patients
400
520,240
300
281,355
200
243,524
100
R2 99.8
0
United States Renal Data System. Annual data
report. 2000.
3
Stage 5 CKD Incidence Rates per Million Vary by
Race/Ethnicity
Incidence Rate per Million (2001)
Odds ratios 1 3.89 2.74
1.56 1 1.45
Plt0.0001Reference population. Data adjusted
for age and gender from 2001 in United States
Renal Data System.2003 Annual Data Report.
Available at www.usrds.org.
4
NHANES III Adjusted Odds of Reduced Kidney
Function
Coresh et al. Am J Kidney Dis. 411-12, 2003
5
Increasing Numbers of Patients May Overwhelm
Nephrologists (amjkd,coresh 2003,nni 1999)
6
Five-Year Outcomes of CKD
RRT renal replacement therapy. Keith et al.
Arch Intern Med. 2004164659-663.
7
Cardiovascular Disease (CVD) Is Linked to Chronic
Kidney Disease (CKD)

• Relative Risk of CVD is 1.4 2.05 X with
• Creatinine gt 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
8
Rates of Death and Cardiovascular Events in
Patients According to GFR
eGFR (mL/min/1.73 m2)
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.
20043511296-1305.
9
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

10
Proteinuria Is a Risk Factor for CVD
Comparison of lowest and highest decile of
microalbuminuria in 7143 nondiabetic patients
Adjusted Hazard Ratio
Primary composite end-point CV death, stroke,
MI. Wachtell et al. Ann Intern Med.
2003139901-906.
11
Microalbuminuria Predicts CV Risk at Levels Below
Current Definition
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
Microalbuminuria
Wachtell K et al. Ann Intern Med.
2003139901-906.
10
12
Proteinuria Is Also a Risk Factor for
Progression of CKD
50
Plt.001
40
30
With Doubling of SCr or ESRD
20
10
0
lt0.5
0.5-3.0
3.0-6.0
gt6.0
Urine Protein (g/d)
P-values are for comparison across the
subgroups. Jafar et al. Kidney Int.
2001601131-1140.
13
Early Treatment Makes a Difference
14
ACE Inhibitors, ARBs, and Combination Therapy in
Nondiabetic Nephropathy
P 0.02
Primary end point doubling of SCr or kidney
failure. Nakao et al. Lancet. 2003361117-124.
15
Features of Hypertensive Nephrosclerosis

• Long history of HTN, prior to known kidney dz.
• No other etiology for kidney disease.
• Proteinuria lt 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

16
Treatment of Hypertension in Nondiabetic Kidney
Disease
http//www.kidney.org/professionals/kdoqi/guidelin
es_bp
17
African Americans Addition of a Diuretic to ARB
Therapy (N440)
Change in systolic BP (mm Hg)
P?0.01 vs placebo. P?0.05 vs placebo. Clin.
Therapeutics, 2001
18
Average Number of Antihypertensive Agents Needed
Per Patient to Achieve Diastolic BP Goals
UKPDS (lt85 mm Hg Diastolic)
ABCD (lt75 mm Hg Diastolic)
MDRD (lt92 mm Hg MAP)
HOT (lt80 mm Hg Diastolic)
AASK (lt92 mm Hg MAP)
1
1.5
2
2.5
3
3.5
4
No. of BP medications
Bakris et al. Am J Kidney Dis. 200036646.
19
African American Study of Kidney Disease and
Hypertension (AASK)

• 1094 patients with HTN and CKD , 4 yr f/uGFR
  20-65 mL/min/1.73 m2
• Excluded DBP lt95 mm Hg, DM, UP/Cr gt2.5

MAP mean arterial pressure DBP diastolic
blood pressure UP/Cr urinary protein to
creatinine ratio. Wright et al for the AASK Study
Group. JAMA. 20022882421-2431.
20
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?

21
Baseline Characteristics (2)
Metoprolol N441
Amlodipine N217
Ramipril N436
2.14 ? 0.75 1.80 ? 0.55
2.28 ? 0.83 1.74 ? 0.55
2.18 ? 0.74 1.76 ? 0.59
Serum Creatinine (mg/dL) Male Female
0.63 ? 1.11 0.44 ? 0.72 31.8
0.57 ? 0.99 0.38 ? 0.73 32.7
0.61 ? 1.01 0.41 ? .75 33.0
Urine Protein (g/d) Male Female with
UP/Cr gt 0.22
Mean ? SD or . No significant differences among
drug groups.
22
Clinical Evidence for Risk Reduction WithACE
Inhibitor or ? Blockade AASK
-20
-22
-38
Metoprolol vs Amlodipine P 0.17
Ramipril vs Metoprolol P 0.04
Ramipril vs Amlodipine P 0.004
Composite risk of rapid GFR decline-decrease from
baseline of 50 or 25 mL/min/1.73 m2, kidney
failure, or death
Patients with existing kidney damage (baseline
UP/Cr gt0.22). Wright et al for the AASK Study
Group. JAMA. 20022882421-2431.
23
Percent Change in Proteinuria from Baseline
172
Amlodipine
Ramipril
122
Metoprolol
82
49
Change (SE)
22
0
-18
-33
0
6
12
18
24
30
36
42
48
Follow-up Month
Geometric mean urine protein/creatinine ratio
declined faster in ramipril and metoprolol
groups than amlodipine group (p lt 0.001)
24
of Patients Reached Urine Protein/Creatinine
Ratiogt0.22
During Follow-up by Drug Group
60
Ramipril vs. Metoprolol p0.014
Amlodipine
Amlodipine vs. Metoprolol p0.009
Ramipril
50
Ramipril vs. Amlodipine plt0.001
Metoprolol
s
t
n
40
e
v
E

30
h
t
i
w
20


10
0
0
6
12
18
24
30
36
42
48
54
60
Follow-up Month
Analysis of patients with UP/Cr lt 0.22 at baseline
25
African American Study of Kidney Disease and
Hypertension (AASK) Trial
Wright et al. JAMA. 20022882421-2431.
26
Role of Angiotensin II in Renal Disease Pathways
TGF- ?
Ang II
PG, NO Afferent dilation
Hypertension
Efferent constriction
Glomerular hypertension
Proteinuria
Extracellular matrix Interstitial fibrosis
PG prostaglandin NO nitric oxide.
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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

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Six Month Change in Proteinuria from Baseline
Predicts Outcome of Kidney Disease Results from
the AASK trial
4.0
2.0
Relative Risk of ESRD
1.0
0.5
0.25
0.125
gt-50
gt-50 to 20
-20 to 25
25 to 100
gt100
Lea J et.al. Arch Intern Med. 2005165947
33
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.

34
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).

35
OBJECTIVE

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

36
African American Study of Kidney Disease and
Hypertension (AASK)

• 1094 patients with HTN and CKD , 4 yr f/uGFR
  20-65 mL/min/1.73 m2
• Excluded DBP lt95 mm Hg, DM or FBSgt140, UP/Cr gt2.5

MAP mean arterial pressure DBP diastolic
blood pressure UP/Cr urinary protein to
creatinine ratio. Wright et al for the AASK Study
Group. JAMA. 20022882421-2431.
37
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 glucosegt110 mg/dl
• triglyceridesgt 150 mg/dl
• HDL chol lt40 mg/dl in men, lt 50 mg/dl in women
• BMIgt30.
• Note BP gt130/85 or on meds was present in all.

38
ATP III The Metabolic SyndromeDiagnosis is
established when ? 3 of these risk factors are
present
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
39
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.

40
RESULTS

• 41 met criteria for metabolic syndrome using
  modified NCEP.
• 40.6 had BMI gt 30 kg/m2 .
• None of the individual components of the MS
  predicted CKD progression in multivariate tests.

41
Baseline Characteristics
42
Cox Regression Analyses with Renal Outcomes
43
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.

44
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.    
45
Cox regression analyses for ESRD alone, ESRD
death

• MS and ESRD alone, HR- 1.73( 1.2-2.5).
• MS and ESRDdeath, HR- 1.62 (1.2-2.2).

46
Cox Model for Metabolic Syndrome and Renal
Outcomes
47
Cox Model for Metabolic Syndrome and Renal
Outcomes
48
Kaplan Meier Survival Curve Metabolic Syndrome
status
49
Strengths and Limitations

• Well-characterized population of
  African-Americans with CKD.
• Iothalamate GFRs to assess renal function.
• No waist circumferences, but BMI used to assess
  obesity.
• 242 missing values- lack of triglycerides.

50
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.

51
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.

52
You Have The Power To Prevent Kidney Disease
53
Perception of increased risk of CKD by patient
characteristic as reported by primary care
physicians
54
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