Transcript Hypertension and Kidney

Management of
hypertension in CKD
 Hypertension is an important cause of
ESRD
 Hypertension is common in patients
with CKD and accelerate the
progression of renal failure
Key Question
Can effective antihypertensive therapy prevent
the development of ESRD and retard the
progression of CKD ?
Age and change of renal function
Prevalence of low GFR
<60 ml/mkn/1.73㎡,%>
40%
30%
20%
10%
0%
40~59
overall
hypertension
60~69
70+
diabetes
no DM and no HT
Three major causes of ESRD
Renal disease
loss of nephrons
Systemic
hypertension
Proteinuria
Progressive
decline
in GFR
CKD:
Common pathway in disease progression
RENAL INJURY
SYSTEMIC
HYPERTENSION
Nephron mass
Glomerular capillary hypertension
Glomerular permeability to macromolecules
Filtration of plasma proteins  Proteinuria
Excessive tubular protein reabsorbtion
Tubulo-interstitial inflammation
RENAL SCARRING
MAJOR RISK FACTORS FOR
CARDIOVASCULAR DISEASE
HYPERTENSION
OBESITY
HYPERLIPIDEMIA
DIABETES
SMOKING
CHRONIC KIDNEY
DISEASE
FAMILY HISTORY
PHYSICAL INACTIVITY
AGE > 55 IN MEN, > 65
IN WOMEN
Why are CKD/ESRD Patients
Predisposed to CV Disease?
CKD/ESRD
ANEMIA
LIPIDS
INFLAMMATION plus CaP
deposition
CAD and PVD
CV DISEASE AND DEATH
LVH/CHF
HTN
Why are CKD/ESRD Patients
Predisposed to CV Disease?
• 30-50% of ESRD patients have INFLAMMATION
(increased CRP, increased IL-6, decreased albumin)
– Increased CRP is a primary marker for inflammation predicting
cardiovascular disease in normal adults
– Increased CRP is the primary marker for increased
cardiovascular mortality on dialysis
• CKD/ESRD patients have metastatic calcification
(coronary arteries) because of secondary
hyperparathyroidism and elevated PO4 levels.
Microalbuminuria and proteinuria as a
risk factor for CAD and CVA – marker
of endovascular health
Miettinen H et al, Stroke 27:2033, 1996
Prevalence of HTN in CKD
80% of patients with
glomerulonephritis
and 30% of patients
with chronic
interstitial disease
are hypertensive.
%
Hypertension and renal function
90
80
normal
hypertension
70
60
50
40
30
20
10
Probability of HT
0
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
stage 1
stage 1
stage 2
stage 2
stage 3
stage 3
stage 4
stage 4
How important is
systemic blood pressure control?
Relative risk of ESRD according to quintile BP
MRFIT study
N= 332,544 men
Hypertension in CKD
Pathophysiology thought to be both pressor- and volumerelated, thus CKD patients respond to both vasodilators as
well as diuretics/sodium restriction.
As kidney function declines closer to ESRD, volumedependent hypertension becomes more important. Often
on dialysis, we can remove antihypertensive agents as we
bring the patient down to their dry weight with ultrafiltration.
Concept of Glomerular Hypertension
• Normally, increased glomerular capillary
pressure (PGC) is good, as it results in
increased GFR.
• Increased PGC is not good in a kidney that
is already damaged = GLOMERULAR
HYPERTENSION.
• Increased PGC occurs with:
 Increased systemic blood pressure
 Increased efferent artery vasoconstriction
(angiotensin II)
 Increased afferent artery dilation (protein
loads, calcium channel blockers)
Angiotensin II plays a central role in organ damage
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction
A II
LV hypertrophy
Fibrosis
Remodeling
Apoptosis
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis
Stroke
Hypertension
Heart Failure
MI
Renal Failure
*Preclinical data.
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate.
Death
Renin Angiotensin Aldosterone
System
Non-ACE pathways




(eg, chymase)
Vasoconstriction
Cell growth
Na/H2O retention
Sympathetic activation
Angiotensinogen
Renin
AT1
Angiotensin I
Angiotensin II
ACE
Aldosterone
Cough,
angioedema
Benefits?
 Bradykinin
Inactive
fragments
AT2
 Vasodilation
 Antiproliferation
(kinins)
Angiotensin II Effects on Glomerular
Capillary Pressure
AA
P
GC
A II
EA
Angiotensin II Causes Glomerular
Hypertension
AA
P
GC
A II
EA
How does blood pressure relate to
progression of CKD?
AA
BP
EA
P
GC
In a sick kidney, increased glomerular capillary
pressure (GLOMERULAR HYPERTENSION) causes
progression of the CKD (increased fibrosis)
Angiotensin II and CKD
Angiotensin II
PGC  Injury to
Glomerular cells 
Proteinuria
.
O2 and TGF- 
Scarring/Fibrosis
Angiotensin II
 One of the most potent vasoconstrictors – critical
in maintenance of blood pressure
 Renal actions
 Increased sodium reabsorption
 Increased GFR by increasing glomerular capillary
pressure
A II Blockade – Experimental data
with diabetic rats at 70 weeks
ACE Inh/ARB 
AII 
BP 
Proteinuria/Renal Disease
14
12
10
% sclerotic 8
glomeruli 6
4
2
0
Glomerular Pressure 40s
rip
le
ap
t
64
D
M
+T
+C
D
M
D
M
C
on
tro
l
Anderson S et al,
Kidney Int 36:526,
1989
46
56
Goals of Treatment of HTN in CKD
• To preserve renal function:
maintain GFR and reduce
proteinuria
• To reduce CV morbidity and
mortality
:most clinical trials in past have
excluded patients with CKD
What should be the treatment goal?
Treatment goal for hypertension in the general
population has remained relatively the same for
the last decade.
Guidelines
BP target
British Hypertension Society
(2004)
JNC VII (2003)
< 140/85
<140/90
Target Blood Pressure
For Individuals With:
BP Goal:
Hypertension
(no diabetes or renal disease)
<140/90 mmHg
(JNC 7)
Diabetes
Mellitus
<130/80 mmHg
(ADA, JNC 7)
Renal Disease
<130/80 mmHg
(JNC 7, K/DOQI)
with proteinuria >1 gram/24 hours or <125/75 mmHg
diabetic kidney disease
(NKF)
Chobanian AV et al. JAMA. 2003;289:2560–2571.
American Diabetes Association. Diabetes Care. 2002;25:134–147.
National Kidney Foundatrion. Am J Kid Dis. 2002;39(suppl 1):S1–S266.
What should be the treatment goal
for renal disease?
Should be lower than the general
population
Should be tailored according to :
 the severity of renal failure
 the severity of the proteinuria
Aggressive BP Control, Proteinuria
and CKD Progression – what is the
optimal BP for CKD?
0
<1 gm/D
-2
1-2.9
gm/D
>3 gm/D
-4
Mean fall
in GFR
-6
(ml/min/yr)
-8
<125/75
<140/90
*
*
-10
-12
Klahr S et al, N Engl J
Med 330:877, 1994
GOAL BP<125/75 if >1 gm proteinuria
Steps to Reduce Renal Disease
Steps every clinician should take to
reduce the incidence and/or
progression of CKD
 Aggressive BP reduction
 Use of agents that interfere with
the RAAS
BP control, GFR decline and proteinuria
Intense
BP
control
An initial reduction in proteinuria of 1.0 g/d  slower mean decrease in GFR
by 0.92 ± 0.31 mL/min·y, GFR 25-55
by 1.32 ± 0.46 mL/min·y, GFR 15-24
Progression of CKD and BP
REIN follow-up trial
chronic nephropathy and proteinuria>3g/day
2
GFR decline (mL/min/1.73m /month)
45
-0.44ml/min per month
40
-0.10ml/min per month
Continued ramipril
35
-0.81ml/min per month
30
-0.14ml/min per month
Switched to ramipril
25
Core study
Follow-up trial
Ruggenenti et al. Lancet 1998;352:1252-1256.
AASK: ACEI vs CCB
in Hypertensive Renal Disease
Cumulative Incidence, %
CCB arm terminated prematurely because ACEI and
beta blocker demonstrated clear superiority
GFR Event, ESRD, or Death
25
P = 0.005
20
15
Amlodipine
10
Ramipril
5
0
0
3
12
24
36
Months
Agodoa LY et al. JAMA. 2001;285:2719–2728.
End-organ damage and mortality in general population
Cardiovascular mortality
Non-cardiovascular mortality
Hans L. Hillege, et al., Circulation, 2002, 106:1777
The Effect of AngiotensinConverting Enzyme Inhibition on
Diabetic Nephropathy
• 409 Type I diabetics ages 18-49 with
nephropathy (U protein>500 mg and S Cr
<2.5)
• Prospective, double-blinded multicenter
(30) trial randomized to captopril vs.
placebo for 3 years
Lewis EJ et al , New Engl
J Med 329:1456-62, 1993
ACE Inhibition and Type I DM Nephropathy
If S Cr > 1.5 mg/dl:
1) Captopril reduced
doubling of S Cr by 48%
over 4 years.
2) Captopril reduced
ESRD(dialysis or
transplant) or death
by 50% over 4 years.
3) These effects were
independent of
effects on blood
pressure.
Lewis EJ et al, New Engl J
Med 329:1456, 1993
Reduction of Endpoints in NIDDM
with the Angiotensin II Antagonist
Losartan – RENAAL
• 1513 Type II diabetics with nephropathy
(U alb/Cr ratio >300 or U prot >500 mg
and S Cr 1.3-3.0 mg/dl)
• Prospective, randomized, doubleblinded multicenter (250) trial
• Two arms – Losartan (50-100 mg) to
keep BP<140/90 vs. placebo for 3.4
years
Brenner BM et al, New Engl J
Med 345:861-869, 2001
RENAAL – ARB Reduction of Renal Failure
16%
25%
28%
20%
Brenner BM et al, N Eng J Med 345:861, 2001
Irbesarten Diabetic
Nephropathy Trial (IDNT)
• 1715 Type II diabetics with hypertension
(BP >135/85) and nephropathy
(proteinuria >900 mg, S Cr 1.0-3.0
mg/dl)
• Prospective, randomized, double-blinded,
multicenter (210) trial
• Three arms: Irbesarten, amlodipine, and
placebo
Lewis EJ et al, New Engl J Med
345:851, 2001
IDNT – ARB Reduction of Renal Failure
20%
23%
33%
Lewis EJ et al, N Eng J Med 345:851, 2001
ARB Effects of Type II DM
Nephropathy - RENAAL and IDNT
Endpoints
RENAAL
IDNT
Composite
16%
20%
S Cr Doubling
25%
33%
ESRD
28%
23%
ACE Inhibitors and CKD Progression
Meta-analysis -Jafar T, Ann Intern Med 135:73-87, 2001
• 11 randomized controlled trials comparing ACE
inhibitors vs. other medications in treatment of
hypertension in 1860 nondiabetic patients with
CKD (S Cr=2.3).
• Results: ACE Inhibitors lowered BP and
proteinuria.
• Results: ACE inhibitors decreased risk of
ESRD by 31%, combined risk of progression
of renal insufficiency and development of
ESRD by 30% independent of BP lowering
effects.
LIFE: Primary Composite Endpoint
16
Intent-to-Treat
Proportion of Patients
With First Event, %
14
Atenolol
There was no
significant difference in
BP between groups at
all time points
12
10
8
Losartan
6
4
Adjusted Risk Reduction 13.0%, P = 0.021
Unadjusted Risk Reduction 14.6%, P = 0.009
2
0
0
6
12
18
24
30
36
42
48
54
60
66
Months
Dahlöf B et al. Lancet. 2002;359:995–1003.
Patients; non-diabetic patients affected by proteinuric
renal disease
MAP > 98 mmHg
Treatment; telmisartan 80mg, once daily
Systolic BP change
Diastolic BP change
mean BP
Proteinuria
135 ± 11 to 122 ± 13 mmHg
84.4 ± 8.1 to 75.9 ± 8.5 mmHg
101 ± 8 to 91 ± 9 mmHg
1.60 ± 0.90 to 1.06 ± 0.63 g/24 h
Cupisti A et al., Biomed Pharmacother, 2003, 57:169
What is the evidence that
combining an ACEI and an
ARB will have additive
benefits?
COOPERATE: Study Design
Design:
Randomized, double-blind trial in 263
patients with non-diabetic renal disease
Primary
Endpoint:
Composite of time to doubling of sCr/ESRD
Randomization:
Losartan 100 mg/day + AHT* as needed
Trandolapril 3 mg/day + AHT* as needed
Duration:
3 yrs
Target BP:
SBP <130 mmHg
DBP <80 mmHg
*Antihypertensive therapy (excluding other ACEIs or other ARBs).
Nakao N et al. Lancet. 2003;361:117–124.
Doubling of Serum Creatinine or Progression to ESRD
Proportion Reaching
Endpoint, %
30
Trandolapril
Losartan
Combination
25
20
15
10
5
P = 0.02
0
0
5
12
18
24
30
36
Months after Randomization
Number at Risk
Losartan
89
Trandolapr
86
Combinati
88
il
on
88
85
87
84
83
86
79
75
83
65
72
76
59
63
73
Nakao N et al. Lancet. 2003;361:117–124.
47
58
67
Additive antiproteinuric effect of ACEI and ARB
in patients with IgA nephropathy
Russo, et al., Am J Kid Dis, 1999, 33
Hypertension and CKD: summary
 Most patients with CKD have hypertension
 Lowering BP (<130/80) important for
reducing CV and renal risk: Lower targets
for proteinuric patients
 Angiotensin blockade slows progression of
CKD independent from BP effects.
ACEI/ARBs first line therapy
 Diuretics/Na restriction often necessary