Epidemiology of
Renal Disease in
Hypertension
Richard Bright, M.D.F.R.S.
1789-1858
Father of Nephrology
Renal Disease in Hypertension
Epidemiology
• Effects of hypertension on the kidney
• Interactions of hypertension and concomitant conditions
on the kidney
–
–
–
–
Age
Atherosclerosis
Diabetes mellitus
Race
• Morbidity & mortality associated with chronic renal disease
– Coronary artery disease
• Progression of chronic renal disease
– End Stage Renal Disease (ESRD)
• Hypertension as a consequence of ESRD
Renal Disease in Hypertension
A Historical Perspective
• Traube (Berlin, 1856) “High Blood Pressure Is Needed”
– Postulated that arterial pressure was elevated to overcome mechanical
resistance against blood flow through thickened arteries.
– Believed that increased blood pressure was necessary for excretory
efficiency of the kidney.
– Promoted these concepts which were unchallenged for almost 80 years.
• Page (Cleveland, 1934) “High Blood Pressure Is NOT Necessary”
– Developed renal clearance techniques that estimated renal blood flow in
humans.
– Reduced elevated blood pressure without a fall in urea clearance.
– Demonstrated that early antihypertensive measures were not detrimental to
renal function.
• Radical sympathectomy in essential & malignant hypertension safely
lowered arterial blood pressure without loss of renal function.
Risk Factors for
Progression of Renal Disease
Can be modified
Cannot be modified
Hypertension
Age
Albuminuria/Proteinuria
Ethnicity
Dyslipidemia
Gender
Hemoglobin A1C
Smoking
Anemia
Ca•P04
ESRD Due to Any Cause
In 332,544 Men Screened for MRFIT
Adjusted Relative Risk§
Adjusted Relative Risk
25.0
22.1*
20.0
15.0
11.2*
10.0
6*
5.0
1.0
1.2
1.9*
3.1*
0.0
Optimal Normal
* p<0.001
Stage 1 Stage 2 Stage 3 Stage 4
High
Normal
Hypertension
Blood Pressure Category
§ Men with optimal blood pressure was the reference category.
Klag MJ, et al. N Engl J Med. 1996;334(1):13-18.
Age-Adjusted Rate of ESRD
Per 100,000 Person-Years
HTN Linked To Chronic Renal Disease Among
332,544 Men Screened for MRFIT
250
200
150
100
110
100-109
90-99
85-89
50
80-84
0
180
160-179
140-159
130-139
120-129
<120
<80
Systolic BP (mm Hg)
Adapted from Klag MJ, et al. N Engl J Med. 1996;334(1):13-18.
© Massachusetts Medical Society
Incidence Rates of Reported
ESRD by Primary Diagnosis
Incidence Per Million
Population
160
Glomerulonephritis
Hypertension
Diabetes
120
80
40
0
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998
Year
United States Renal Data System (USRDS)
2000 Annual Data Report • WWW.USRDS.ORG
Primary Diagnoses for
Patients Who Start Dialysis
Other
10%
Glomerulonephritis
13%
Diabetes
50%
Hypertension
27%
United States Renal Data System (USRDS)
2000 Annual Data Report • WWW.USRDS.ORG
Persons Initiating Treatment for
ESRD Related to Diabetes in the US
Number of People
35,000
30,000
25,000
20,000
15,000
10,000
5,000
0
1984
1986
1988
1990
Year
CDC Diabetes Surveillance, 1997.
1992
1994
1996
Global Estimates and Projections
for Incidence of Diabetes Mellitus
Type I Diabetes
Type II Diabetes
250
25
200
In Millions
In Millions
20
15
10
150
100
5
50
0
0
1997
2010
Year
Amos A, McCarty D, Zimmet P.
Diabetes Medicine. 1997;14[Suppl5]:S1-85.
1997
2010
Year
Odds Ratio For ESRD By Race
Racial differences in ESRD in the USA from 1990 to 1998
5
4.45*
3.57*
Odds ratio
4
3
2
1
1.59 *
1.00
reference
0
White
Black
* p <0.0001
United States Renal Data System (USRDS)
2000 Annual Data Report • WWW.USRDS.ORG
Native
Asian
Effect of Hypertension on Mortality
in Diabetic Pima Indians
Age-Adjusted Death Rates for Diabetic Nephropathy
*
Adjusted Death Rate
(x1000/year)
3.5
3
2.5
2
1.5
1
0.5
0
*p <0.001
Normotensive
Diabetics
N=10 deaths
Sievers ML, et al. Circulation. 1999;100(1):33-40.
Hypertensive
Diabetics
N=75 deaths
Risk of Ischemic Heart Disease
Related to SBP and Microalbuminuria
N=2,085; 10 year follow-up
Relative Risk
6
5
Normoalbuminuria
Microalbuminuria
4
3
2
1
0
SBP <140
SBP 140-160
Borch-Johnsen K, et al.
Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
SBP>160
Microalbuminuria Compared To Traditional
Risk Factors For Ischemic Heart Disease
N=2,085; 10 year follow-up
2.5
2
1.5
P
to
lic
Sy
s
C
al
To
t
Borch-Johnsen K, et al.
Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
B
l
te
ro
ho
le
s
G
en
e
M
al
m
in
ur
ia
al
bu
M
ic
ro
Sm
0.5
de
r
1
ok
in
g
Relative Risk
3
Crude Incidence Rates of
End Stage Renal Disease, By Race
Patients per million population
Racial differences in ESRD in the USA from 1990 to 1998
800
White
Black
Native
Asian
600
400
200
0
1990 1991 1992 1993 1994 1995 1996 1997 1998
Year
United States Renal Data System (USRDS)
2000 Annual Data Report • WWW.USRDS.ORG
Comorbidities in
Renal Disease Patients (1999)
COPD
Diabetes on insulin ‡
Diabetes mellitus §
History of hypertension
Peripheral vascular
CVA/TIA
Cardiac dysrhythmia
Myocardial infarction
Ischemic heart disease
Congestive heart failure
0
20
40
60
Percent of Total Patients
§ Diabetes mellitus as a primary or contributing diagnosis.
‡ Diabetes mellitus that requires insulin treatment, which is a subset of the diabetes category.
United States Renal Data System (USRDS)
2000 Annual Data Report • WWW.USRDS.ORG
80
Crude Incidence Rates of
Reported End Stage Renal Disease
Patients per million
population
400
300
200
100
0
1990
1992
1994
Year
United States Renal Data System (USRDS)
2000 Annual Data Report • WWW.USRDS.ORG
1996
1998
Racial Distribution for Comorbidities
In Dialysis Patients (1999)
Percent of Patients
100
80
Black
Asian
Native
White
60
40
20
0
History of
Hypertension
Diabetes§
Congestive
Heart Failure
Diabetes‡
Insulin Treated
§ Diabetes mellitus as a primary diagnosis or contributing diagnosis.
‡ Diabetes mellitus that requires insulin treatment, which is a subset of the diabetes category.
United States Renal Data System (USRDS)
2000 Annual Data Report • WWW.USRDS.ORG
Annual % Mortality (Log Scale)
CV Mortality in General Population
(GP) & Dialysis Patients, By Race
100.000
10.000
1.000
0.100
GP Black
GP White
Dialysis Black
Dialysis White
0.010
0.001
25-34
35-44
45-54
55-64
Age (years)
Sarnak MJ, Levey AS. Semin Dial. 1999;12:69-76.
65-74
75-84
85+
Hypertension and Chronic Renal Disease:
Hemodynamic Abnormalities
Mean BP =
Cardiac
Output
Increased Cardiac Output
Intravascular Volume




Glomerular filtration
Sodium excretion
Extracellular Fluid
Renal Nerve Activity
Myocardial Performance
 Adrenergic Activity
X
Total Systemic
Vascular Resistance
Increased
Vasoconstriction
 Adrenergic Stimuli
 Angiotensin II
 Endothelin
 Endothelium-derived
Contracting Factors
 Thromboxane
Decreased
Vasodilation
 Prostacyclin
 Nitric oxide
 EDHF*
*Endothelium-derived
Hyperpolarizing Factors
Textor SC. Atlas of Diseases of the Kidney, 2001.
Prevalence of Hypertension
In Chronic Renal Diseases
Hypertension Prevalence (%)
80
70
60
50
40
30
20
10
0
MCN
CIN
IgA
MGN
APKD
DN
MPGN FSGN
MCN=minimal change nephropathy CIN=chronic interstitial nephritis IgA=IgA nephropathy
MGN=membranous glomerulonephritis APKD=adult-onset polycystic kidney disease DN=diabetic nephropathy
MPGN=membranoproliferative glomerulonephritis FSGN=focal segmental glomerulonephritis
Smith MC and Dunn MJ, in Hypertension.
Laragh JH, Brenner BM. Raven Press; 1995:2081-2101.
trc.ucdavis.edu/mjguinan/apc100/modules/
Urinary/mammal/cortex1/cortex.html
trc.ucdavis.edu/mjguinan/apc100/modules/
Urinary/mammal/glomeruli0/glomeruli.html
Hypertension and
Renal Disease:
Mechanisms
Scanning electron (top) and
light (bottom) micrographs of
a human glomerulus
Components of the Normal Nephron
Bowman’s
Capsule
Glomerulus
Proximal Convoluted
Tubule
Mesangial Matrix
Adventitial Mast
Cell/Macrophage
Mesangial Cells
Vascular Smooth
Muscle Cells
Macula
Densa
Renal Sympathetic
Nerves
Juxtaglomerular
Cells
Distal
Convoluted Tubule
Efferent Renal
Arteriole
Mechanisms of Renal Damage in HTN
Mechanisms
•Glomerular hypertension
•Hyperfiltration
•Glomerular barrier
dysfunction
Normal Kidney
•Proteinuria
•Mesangial cell
hyperplasia
•Intrarenal inflammatory
processes
•Endothelial dysfunction
•VSMC proliferation
Blood
Pressure
Consequences of Renal Damage in HTN
Consequences
Functional
Renal Failure
•Decrease in GFR
•Proteinuria
Structural
•Glomular basement
membrane changes
•Expanded mesangial
matrix
•Glomerulosclerosis
Blood
Pressure
•Tubulo-interstitial
fibrosis
Effects of Vasodilators
in the Normal Kidney
L-Arginine
L-Citrulline
eNOS
NO
(-)
EDHF(s)
(-)
(-)
VSMC
Pgl2
(-)
(-)
EC
M
PMN
Platelet
Imbalance in Factors Affecting
Vascular Tone and Structure
Nephron destruction
and renal failure
Vascular tone
and structure
EDHF= endothelium-derived
hyperpolarizing factors
ROS= reactive oxygen
species
EDCF= endothelium-derived
constricting factors
ROS Reduces the
Biological Effects of NO
L-Arginine
L-Citrulline
eNOS
_
(-)
•
NO + O2 = OONO
(+)
NE
Mast
cell
Fibroblast
VSMC
EC
M
PMN
Afferent Arteriole
Renin-Angiotensin Cascade
Angiotensinogen
Non-renin
(eg tPA)
Renin
Bradykinin
 Angiotensin I
Non-ACE
(eg chymase)
ACE
 Angiotensin II
AT1
AT2
ATn
Inactive
peptides
Angiotensin II (Ang II) generated
in the afferent arteriole interacts
with AT1 receptors on cellular
components of the nephron
Angiotensinogen
Ang I
ACE
Renin
Ang II
AT1R
= AT1 Receptor
Role of Angiotensin II
in Chronic Renal Disease






•Mechanical stress
•Mesangial changes
•Oxidative stress
•Proteinuria
•NF-B activation
Adhesion molecules
Chemotactic factors
Cell growth
Apoptosis
TGF-, CTGF
PAI-1
Angiotensin II
 Glomerular capillary
pressure
 Single nephron GFR
Renal
disease
Adapted from Berk B. 2001.
Macrophage
infiltration
Glomerulosclerosis
Nephron
loss
& Tubulo-interstitial
fibrosis
Angiotensin II Induces
Oxidative Stress in the Kidney
• Stimulation of Membrane NOX-1 Oxidase*
–
–
–
–
Increased
Increased
Increased
Increased
superoxide (O2)
thiobarbituric acid reactive substances
oxidized lipids
tissue protein carbonyl content
• Induction of Heme Oxidase-1 (HO-1)
• Activation of NF-B
– Increased inflammatory cytokines
*NAD(P)H Oxidase
Renal Sources of ROS
Superoxide
dismutase
•
•
•
•
•
•
NOX-1 oxidase*
Xanthine oxidase
Heme oxygenase–1
Cyclo-oxygenase
Lipoxygenase
Cytochrome P450
mono-oxygenase
• Mitochondrial
oxidative
phosphorylation
*NADP(H) oxidase
O2
•
O2
Catalase
H 2 O2
H2O+O2
Oxidative Stress: Endothelial
Dysfunction and CAD/Renal Risk Factors
Hypertension
Diabetes
Smoking
LDL
Homocysteine
Estrogen
deficiency
 O2
Endothelial Cells and
 H2O2 Vascular Smooth Muscle
Endothelial Dysfunction
Apoptosis
Leukocyte
adhesion
Lipid
deposition
Vasoconstriction
VSMC
growth
Thrombosis
Pivotal Role of ROS in Stimulus-Induced EC and
VSMC Growth, Survival, and Apoptosis
Growth/Death
Survival Signals
Sources of
ROS
Potential
Targets
of ROS
PDGF, Thrombin, Norepinephrine, Ang II, TNF,
Ox-LDL, High Glucose, VEGF
Arachidonate
Metabolism
Cytochrome
P450
Mitochondrial Electron
Transport Chain
 JNKs
Growth or
Hypertrophy
NOX-1 Oxidase
ROS
SAPKs
 p38MAPK
Xanthine
Oxidase
 ERKs
 Akt
Survival
 NF-B
  Caspases
Apoptosis
Pathologic Processes Leading to
Glomerular Injury and Proteinuria
Glucose
Glycoxidation
(glycation)
AGEs
Increased
glomerular
pressure
Ang II
Urinary protein
=angiotensin AT1
receptor
Efferent
arteriolar
constriction
Ang II
Fibrosis and Nephron Loss:
A Renal Response to Injury
Vascular and/or Tubular Injury
Glomerular cells Tubular cells
Lymphocytes Macrophages
Fibroblasts
FIBROSIS
TGF-
ET-1
CTGF
Ang II
PAI-1
PDGF
bFGF
TNF-
IL-1
TGF-
TGF- plays a key
role in extracellular
matrix formation in
mesangium
and interstitium
that leads
to fibrosis and loss
of nephron units
•
O2
Ang II
bFGF
PDGF
TSP1
TGF-
•
O2
TGF- plays a key
role in extracellular
matrix formation in
mesangium
and interstitium
that leads
to fibrosis and loss
of nephron units
Proteases
(-)
(-)
•
O2
TIMP
(+)
PAI-1
Ang II
(+)
(+)
PDGF
bFGF
TSP1
ET-1
TGF-
•
O2
TGF- plays a key
role in extracellular
matrix formation in
mesangium
and interstitium
that leads
to fibrosis and loss
of nephron units
Angiotensin II: Role in Renal Injury
Angiotensin II
+
Angiotensinogen
Fibroblasts
Proliferation and
differentiation
AT1R
AT2R
TNFR1
+
TNFR2
NF-B
Profibrotic
cytokines
Matrix
FIBROSIS
TNF-
Tubule cells
Cellular adhesion
molecules
Inflammation
Aldosterone Promotes Renal Fibrosis
by Multiple Mechanisms
Angiotensin II
Adrenal
Vascular
Aldosterone
PAI-1
Stimulates
Inhibits
Na+ influx
into VSMC
Fibroblast
collagen
synthesis
AT1R binding
of Ang II
Nitric oxide
synthesis
Norepinephrine
uptake
into VSMC
Pathways Leading To
Progressive Renal Failure
Renal injury
Renal growth
factor & cytokine
activation
Systemic
hypertension
Nephron mass
Glomerular hypertension
Progressive Loss of
Filtration Surface Area
Transdifferentiation
of renal cells to
fibroblast
Influx of
phenotype
monocytes
and macrophages
Fibrogenesis
Brenner BM, Keane WF. 2001.
GFR
Renal scarring
Filtration of plasma
proteins
(Proteinuria)
 Proximal tubule
protein uptake
Hyperlipidemia
Renal
microvascular
injury
Los 100 mg + Other
Antihypertensive Therapy
(excluding ACEI, AIIA)
Los 100 mg
Los 50 mg
NIDDM Patients
with proteinuria
Maintain prior
antihypertensive
therapy
(excluding ACEI,
AIIA)
n = 1520
Goal BP
< 140/90 mmHg
Placebo
Placebo
Placebo + Other
Antihypertensive Therapy
(excluding ACEI, AIIA)
Clinical Trials in
Hypertension and
Renal Diseases
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
Renal Disease and Hypertension
Core Concepts of Treatment
• Hypertension and proteinuria (albuminuria)
are both independent variables that predict
long-term decline in renal function
 Renal disease is both a cause and
consequence of hypertension
 Reduction of blood pressure reduces
cardiovascular risk and renal risk
 Reduction of proteinuria (albuminuria) may
lower both cardiovascular risk and renal
risk
Meta Analysis: Lower Mean BP
Results in Slower Rates of Decline in
GFR in Diabetics and Non-Diabetics
MAP (mmHg)
95
98
101
104
107
110
113
116
119
GFR (mL/min/year)
0
-2
r = 0.69; P < 0.05
-4
-6
Untreated
HTN
-8
-10
-12
130/85
-14
140/90
Parving HH, et al. Br Med J. 1989. Moschio G, et al. N Engl J Med. 1996.
Viberti GC, et al. JAMA. 1993.
Bakris GL, et al. Kidney Int. 1996.
Klahr S, et al. N Eng J. Med 1994. Bakris GL. Hypertension. 1997.
Hebert L, et al. Kidney Int. 1994. The GISEN Group. Lancet. 1997.
Lebovitz H, et al. Kidney Int. 1994.
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
Reprinted by permission, Harcourt Inc.
Meta Analysis: Lower Systolic BP
Results in Slower Rates of Decline in
GFR in Diabetics and Non-Diabetics
SBP (mmHg)
130
134
138
142
146
150
154
170
180
GFR (mL/min/year)
0
-2
r = 0.69; P < .05
-4
-6
Untreated
HTN
-8
-10
-12
-14
Parving HH, et al. Br Med J. 1989. Moschio G, et al. N Engl J Med. 1996.
Viberti GC, et al. JAMA. 1993.
Bakris GL, et al. Kidney Int. 1996.
Klahr S, et al. N Eng J Med. 1994. Bakris GL. Hypertension. 1997.
Hebert L, et al. Kidney Int. 1994. The GISEN Group. Lancet. 1997.
Lebovitz H, et al. Kidney Int. 1994.
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
Goal BP Recommendations for
Patients with DM or Renal Disease
Systolic
Organization
Year
BP
American Diabetes Association 2001
<130
Diastolic
BP
<80
2000
<130
<80
Canadian Hypertension Society 1999
<130
<80
1999
<140
<80
1999
<130
<85
1997
<130
<85
National Kidney Foundation
British Hypertension Society
WHO & International
Society of Hypertension
Joint National Committee
(JNC VI)
JNC-VI General Goals for BP Control
Pre-existing
condition
% achieved
BP goals
BP goals
(mmHg)
Essential
Hypertension
27%
<140/90
Diabetes
11%
<130/85
Renal Disease
and proteinuria
>1.0 gram/24 h
<10%
<125/75
Coresh J, et al. Arch Intern Med. 2001;161(9):1207-1216.
Frequency of Proteinuria
(Albuminuria) in the United States
Adults With Proteinuria
Quantitation
Increased urine ratio
albumin/creatinine
Total adults % of adults
(in millions)
in US
20.2
11.7
18.3
10.6
1.9
1.1
(>30 mg/gm)
Proteinuria
(>300mg/24h)
Microalbuminuria
(30-300 mg/24h)
Keane WF, Eknoyan G. Am J Kidney Dis.
1999;33(5):1004-1010
Impact of Blood Pressure Reduction
on Mortality in Diabetes
Trial
Conventional Intensive
Risk
care
care
reduction
P-value
UKPDS
154/87
144/82
32%
0.019
HOT
144/85
140/81
66%
0.016
Mortality endpoints are:
UK Prospective Diabetes Study (UKPDS) – “diabetes related deaths”
Hypertension Optimal Treatment (HOT) Study – “cardiovascular deaths” in diabetics
Turner RC, et al. BMJ. 1998;317:703-713.
Hansson L, et al. Lancet. 1998;351:1755–1762.
UK Prospective Diabetes Study (UKPDS)
Major Results: Powerful Risk Reductions
Better blood pressure control reduces…
• Strokes by > one third
• Serious deterioration of vision by > one third
• Death related to diabetes by one third
Better glucose control reduces…
• Early kidney damage by one third
• Major diabetic eye disease by one fourth
Turner RC, et al. BMJ. 1998;317:703-713.
Diabetes: Tight Glucose vs Tight BP
Control and CV Outcomes in UKPDS
% Reduction In Relative Risk
0
Stroke
DM
Deaths
Any Diabetic
Endpoint
Microvascular
Complications
5%
-10
10%
12%
-20
24%
*
-30
32%
*
-40
-50
32%
*P <0.05 compared to tight glucose control
44%
*
37%
*
Tight Glucose Control
Tight BP Control
(Goal <6.0 mmol/l or 108 mg/dL)
(Average 144/82 mmHg)
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
Reprinted by permission, Harcourt Inc.
UKPDS: Relationship Between BP Control
And Diabetes-Related Deaths
Hazard ratio
5
1
p<0.0001
17% decrease per 10 mmHg decrement in BP
0.5
110
120
130
140
150
Mean systolic blood pressure (mmHg)
Adler AI, et al. BMJ. 2000;321:412-419.
Reprinted by permission, BMJ Publishing Group.
160
170
HOT Trial: BP Control Reduces
Cardiovascular Events in Diabetics
30
Target
Diastolic
BP
Number of
Patients
(mmHg)
Achieved†
Systolic
BP
Achieved†
Diastolic
BP
(mmHg)
(mmHg)
 90
501
143.7
85.2
 85
501
141.4
83.2
 80
499
139.7
81.1
Achieved = Mean of all BPs from 6 months of
follow-up to end of study
Major CV events*
1000 patient-yrs
Diabetes Subgroup
25
20
P < .005
24.4
18.6
15
11.9
10
5
†
0
*includes all myocardial infarction, all strokes,
and all other CV deaths
Hansson L, et al. Lancet. 1998;351:1755–1762.
Landmark ACE Inhibitor
Trials in Diabetics
Study
Lewis
Drug
Captopril
N
Dosing
Study
years
Endpoint
P-value
~3
Doubling of
serum
creatinine
P=0.007
P=0.026
NS
409
25 mg tid
~3
Correlation of
MAP w/ rate of
change in GFR
5
24-hr creatinine
clearance
Lebovitz
Enalapril
165
5-40
mg qd
ABCD
Trial
Enalapril
470
5-40
mg qd
ABCD = Appropriate Blood Pressure Control in Diabetes Trial
Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.
Lebovitz HE, et al. Kidney Int. 1994;45(suppl45):S150-S155.
Estacio RO, et al. Diabetes Care. 2000;23(suppl2):B54-B64.
ACE-I Is More Renoprotective Than
Conventional Therapy in Type 1 Diabetes
100
% with
doubling of
baseline
creatinine
Baseline creatinine >1.5 mg/dL
75
Placebo
n=202
50
P<.001
25
Captopril
n=207
0
0
1
2
Years of follow-up
Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.
3
4
ACE-I Is More Renoprotective than
Conventional Therapy in Type 1 Diabetes
P<.001
20
0
-20
-40
-60
Placebo
2
Decrease in mean arterial
pressure (mmHg)
% change in proteinuria
40
0
2
-4
-6
-8
Captopril
Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.
NS
Placebo
Captopril
Relationship of Achieved Mean Arterial
Pressure to Parameters of Renal Function
in Type 1 Diabetes
Mean
arterial
pressure
(mmHg)*
n
< 92
47
Final total
proteinuria(mg/24h)
Serum
creatinine
(mg/dL)
GFR
(mL/min)
# patients
with final
proteinuria
<500 mg/24h
1,073 + 1,535† (418)
+0.14†
-5.2†
27
+0.38
-6.2
11
+0.38
-11.6
2
+0.92
-11.0
0
92.1–99.9 41 1,830 + 1,701 (1,798)
100–107
107.1
32 4,249 + 4,754 (2,659)
6
4,882 + 2,878 (5,825)
Note: Values expressed as mean + SD. Data based on achieved blood pressures, not
randomized blood pressure goals.
*Mean of all pressure readings observed during the trial for each patient.
† P < 0.05 when < 92 group is compared with these patients with MAP >92.1 mmHg.
Lewis JB, et al. Am J Kidney Dis. 1999;34(5):809-817.
Impact of ACE-I on BP and GFR:
Acute and Chronic Effects
90
155
140
*
*
*
125
Baseline 1 Month 5.6 Yrs Month off
ACE-I
+Clonidine
GFR ml/min/1.73m2
SBP (mmHg)
170
85
80
*
75
*
70
65
60
Baseline 1 Month
*P<0.05 compared to baseline
Bakris GL, Weir MR. Arch Intern Med. 2000;160(5):685-93.
©American Medical Association
5.6 Yrs Month off
ACE-I
+Clonidine
ARB (Losartan) Reduces Urinary Albumin and
TGF-1 in Type 2 Diabetes with Microalbuminuria
130
120
90
mmHg
24-hour Systolic BP
P<0.01 vs baseline
80
90
Urinary Albumin Excretion
P<0.01 vs baseline
80
70
60
24-hour Diastolic BP
P<0.03 vs baseline
70
60
mcg/min
140
100
50
6
ng/mL
mmHg
160
5
4
3
2
1
Baseline 4 Weeks 8 Weeks
Esmatjes E, et al. Nephrol Dial Transplant.
2001;16(Suppl1):90-93.
TGF-
P<0.005 vs baseline
Baseline
4 Weeks
8 Weeks
Landmark Trials in Diabetics and Non-Diabetics
with ESRD/Death as an Endpoint
Trial
Year
Endpoint
significance
Achieved BP
Captopril
1993
P=0.007
141/82
AIPRI
1996
P<0.001
139/82
REIN
1997
P=0.03
142/84
RENAAL
2001
P=0.01
142/77
IDNT
2001
results pending
results pending
Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.
Maschio G, et al. N Engl J Med. 1996;334(15):939-945.
The GISEN Group. Lancet. 1997;349:1857–1863.
Landmark Renal Trials in
Non-Diabetics with ACE Inhibitors
Study
Drug
Dosing
Survival
Benefit
Study
Duration
AIPRI
Benazepril
10-20
mg qd
P<0.001
~3.0 years
REIN
Ramipril
5-10
mg qd
P=0.03
~ 3.5 years
AIPRI = ACE Inhibition in Progressive Renal Insufficiency Study
REIN = Ramipril Efficacy In Nephropathy Study
Maschio G, et al. N Engl J Med. 1996;334(15):939-945.
The GISEN Group. Lancet. 1997;349:1857-1863.
AIPRI: Baseline Prognostic Factors and Reduction of
Risk for Progressive Renal Insufficiency with ACE-I
Creatinine Clearance
0
>45 ml/min
≤45 ml/min
24-Hr Urine Protein Excretion
≤1gm
>1 to <3gm
≥3gm
% risk reduction
-10
-20
31%
-30
-40
46%
53%
-50
-60
-70
71%
-80
Maschio G, et al. N Engl J Med. 1996;334(15):939-945.
66%
% of patients without
combined endpoint*
REIN Study: ACE Inhibition in Proteinuric
Non-Diabetic Nephropathy
100
80
Ramipril
60
40
P=0.02
20
0
Placebo
0
6
12
18
24
30
36
Baseline SBP
∆ SBP
Baseline DBP
∆ DBP
Ramipril
149.8
-5.8 mmHg
92.4
-4.2 mmHg
Placebo
148.0
-3.4 mmHg
91.3
-3.4 mmHg
*Combined endpoint = doubling of baseline serum creatinine concentration or end stage renal failure
The GISEN Group. Lancet. 1997;349:1857–1863.
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
% pts with doubling
of baseline Cr or ESRD
Mean rate of GFR decline
(mL/min/month)
REIN Study: ACE Inhibition in Proteinuric
Non-Diabetic Nephropathy
n = 61 n = 36
3–4.5 4.5–7.0
n = 20
 7.0
Baseline urinary
protein excretion
(g/24 h)
The GISEN Group. Lancet. 1997;349:1857–1863.
70
60
50
40
30
20
10
0
Placebo
Ramipril
n = 87 n = 48 n = 31
3–4.5 4.5–7.0  7.0
Baseline urinary
protein excretion
(g/24 h)
REIN Study: Ramipril Group Median
Change in Urinary Protein Excretion
0
1
3
Months
6
% change in urinary
protein excretion
0
-10
-20
-30
-40
-50
-60
The GISEN Group. Lancet. 1997;349:1857–1863.
12
24
36
ACE-I Provides Greater Renoprotection
Than Non-ACE-I in Patients with
Diabetic and Non-Diabetic Nephropathy
Study
Bjork et al
Lewis et al
REIN
MicroHOPE
AASK
Year
Conclusions about
ACE inhibitors (ACE-I)
1992
ACE-I reduced both the rate of decline in GFR and the
amount of albuminuria.
1993
In Type I diabetics, ACE-I reduced proteinuria, risk of
doubling serum creatinine, and risk of ESRD+Death.
But, ESRD alone was not reduced.
1997
In non-diabetics, ACE-I reduced proteinuria, risk of
doubling serum creatinine, and risk of ESRD+Death.
But, ESRD alone was not reduced.
2000
ACE-I reduced progression of proteinuria from
normoalbuminuria to microalbuminuria and from
microalbuminuria to macroalbuminuria.
2001
ACE-I was superior to amlodipine in reducing proteinuria
among non-diabetic African Americans with
hypertension and kidney disease.
AASK: The African American Study
of Kidney Disease and Hypertension
• The AASK trial enrolled 1,094 African American
patients with renal disease at 21 US centers, and
randomized them to receive one of 3 study drugs:
– Ramipril – ACEI or
– Amlodipine – CCB or
– Metoprolol – Beta-blocker
• Results
– After adjustments for covariates, the risk
reduction for ramipril vs amlodipine groups in the
clinical composite outcomes (GFR, dialysis, or
death) was 38% (p=0.005)
Agodoa L, et al. JAMA. 2001;285(21):2719-2728.
HOPE TRIAL:
Independent Predictive Variables for Combined
Endpoints of CV Death, MI, and Stroke
Variable
Hazard Ratio
Microalbuminuria
1.59
Creatinine > 1.4 mg/dL
1.40
CAD
1.51
PVD
1.49
1.42
Diabetes Mellitus
Age
1.20
1.03
Waist-Hip Ratio
1.13
Male
Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.
HOPE Trial:
Main Outcomes and Serum Creatinine
Events per 1000 Person-Years, n
All Patients
80
60
60
Primary
Outcome*
50
40
40
40
30
<1.4 mg/dL
>1.4 mg/dL
10
0
60
Cardiovascular
Death*
50
40
*p=<0.001
Myocardial Infarction*
<1.4 mg/dL
>1.4 mg/dL
All Death*
30
20
10
20
10
0
Ramipril
30
20
20
0
Placebo
<1.4 mg/dL
>1.4 mg/dL
0
Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.
Reprinted by permission, ACP-ASIM.
<1.4 mg/dL
>1.4 mg/dL
HOPE Trial:
Primary Outcomes and Serum Creatinine
Events per 1000 Person-Years, n
Placebo
100
80
60
Ramipril
100
Diabetic
Patients
80
60
40
40
20
20
0
100
80
<1.4 mg/dL
>1.4 mg/dL
Non-Diabetic Patients
0
100
80
60
60
40
40
20
20
0
0
<1.4 mg/dL
Hypertensive Patients
>1.4 mg/dL
Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.
Reprinted by permission, ACP-ASIM.
<1.4 mg/dL
>1.4 mg/dL
Normotensive Patients
<1.4 mg/dL
>1.4 mg/dL
Comparison of Anti-Hypertensive
Regimens on Proteinuria
With similar reductions of blood pressure…
• Dihydropyridine calcium channel blockers (DHPCCB)
increase proteinuria
− Ref: Mimran A, et al. Diabetes Care. 1988;11:850-853.
− Ref: Demarie BK, Bakris GL. Ann Intern Med. 1990;113:987-988.
− Ref: Agodoa L, et al. JAMA. 2001;285(21):2719-2728.
• Non-DHPCCB reduces proteinuria when a DHPCCB
produces no change or increase in proteinuria
– Ref: Smith AC, et al. Kidney Int. 1998;54:889-896.
– Ref: Kloke H, et al. Kidney Int. 1998; 53:1559-1573.
Mean Changes in Albuminuria and
Mean Arterial Pressure (MAP) in Studies
of Patients with HTN and Proteinuria
Percent Change
20
10
Other
Diltiazem &
All
Dihydropyridine Verapamil
Nifedipine
ACE Inhibitors
CCBs
CCBs
N=173
N=121
0
-10
-20
-30
-40
MAP(mmHg)
Albuminuria
-50
Kloke H, et al. Kidney Int. 1998;53:1559-1573.
N=111
N=723
ACE-I + Verapamil: Additive Reduction of
Proteinuria in Type 2 Diabetes at 1 Year
Percent reduction
0
Trandolapril
(5.5 mg/d)
n=12
Verapamil Trandolapril (2.9 mg/d)
(315 mg/d) + Verapamil (219 mg/d)
n=11
n=14
-10
-20
-30
-27%
-33%
-40
-50
-60
MAP
Proteinuria
-70
-62%
*
*p <0.001 combination vs either monotherapy
Bakris GL, et al. Kidney Int. 1998;54:1283-1289.
Reprinted by permission, Blackwell Science, Inc.
Therapeutics in
Hypertension and
Renal Diseases
Renal Diseases in Hypertension
Core Concepts of Treatment
• Hypertension is an independent variable that predicts long-term
decline in renal function
• Proteinuria is also an independent variable that predicts longterm decline in renal function
• Reduction of blood pressure reduces both cardiovascular and
renal risk
• Reduction of proteinuria may reduce both cardiovascular and
renal risk
• Relative renal hypoperfusion during initial stages of therapy for
hypertension is associated with a transient limited rise in serum
creatinine and is not a reason to stop therapy
Risk Stratification: JNC-VI
Risk Group
A
•No risk
factors
•No TOD
•No CCD
Risk Group
B
•>1 risk
factors…but
no diabetes
•No TOD
•No CCD
Risk Group
C
•Diabetes
and/or
•TOD & CCD
•+ Other risk
factors
Lifestyle
modification
Drug
therapy§
BP
Stages
Systolic
BP
(mmHg)
Diastolic
BP
(mmHg)
High
Normal
130139
85-89
Lifestyle
modification
Lifestyle
Lifestyle
modification
modification Drug therapy
(up to 12
(up to 6 mos)
mos)
Stage 1
140159
90-99
Stage
2&3
> 160
> 100
Drug
therapy
Drug
therapy
Drug therapy
TOD = Target Organ Damage; CCD = Clinical Cardiovascular Disease
§For those patients with heart failure, renal insufficiency, and diabetes mellitus
JNC-VI. Arch Intern Med. 1997;157(21):2413-2446.
JNC-VI Treatment Recommendations
for High Risk Hypertensives
BP Stage
Risk Group C
•Diabetes…and/or
Systolic BP Diastolic BP •TOD & CCD
• Other risk factors
(mmHg)
(mmHg)
High Normal 130-139
Stage 1
140-159
85-89
Drug therapy§
90-99
Drug therapy
TOD = Target Organ Damage; CCD = Clinical Cardiovascular Disease
§For those patients with heart failure, renal insufficiency, and diabetes mellitus
JNC-VI. Arch Intern Med. 1997;157(21):2413-2446.
WHO-ISH 1999 Guidelines for Management
of HTN: CV Risk and Prognosis
Systolic and Diastolic BP (mmHg)
Grade 1
Mild HTN
SBP 140-159
or DBP 90-99
Grade 2
Moderate HTN
SBP 160-179
or DBP 100-109
Grade 3
Severe HTN
SBP 180
or DBP 100
No other risk
factors
Low risk
Medium risk
High risk
II
1-2 risk factors
Medium risk
Medium risk
Very high
risk
III
 3 risk factors or
TOD or DM
High risk
High risk
Very high
risk
IV
Associated
clinical conditions
Very high
risk
Very high
risk
Very high
risk
Risk
strata
Other risk factors
& disease history
I
TOD=Target Organ Damage/Associated Clinical Conditions
include clinical cardiovasular disease or renal disease
WHO-ISH Guidelines. J Hypertens. 1999;17(2):151-183.
©Lippincott, Williams & Wilkins • www.lww.com
Treatment of
High Risk Hypertensives
Patient type
BP treatment
goal
# drugs
required
High risk
group C
<130/80
~2-3
Diabetics with
>1gm
Proteinuria
<125/75
~3-4
Average Number of Anti-Hypertensive
Agents Used to Achieve Target BP
Goal BP
Achieved
BP
Avg # of
drugs per
patient
MDRD
ABCD
HOT
UKPDS
<92 mmHg
MAP*
<75
mmHg
DBP
93
~75
81
82
3.6
2.7
3.3
2.8
<80 mmHg <85 mmHg
DBP
DBP
*The goal mean arterial pressure (MAP) of <92 mmHg specified in the MDRD trial
corresponds to a systolic/diastolic blood pressure of approximately 125/75 mmHg.
Physician Practices in Treating
HTN With and Without Diabetes
40-60y/no DM
40-60y/with DM
>70y/no DM
>70y/with DM
% of respondents
60
50
40
30
20
10
0
80-84
85-89
90-94
95-99
DBP (mmHg) to Start Treatment
Hyman DJ, Pavlik VN. Arch Intern Med. 2000;160(15):2281-2286.
Reprinted by permission, American Medical Association.
100-110
Anti-Hypertensive Drugs:
Sites of Action
Blood
Pressure
=
Cardiac
Output
-Blockers
CCBs*
Diuretics
* = non-dihydropyridine CCBs
X
Total
Peripheral
Resistance
ACE Inhibitors
AT1 Blockers
a-Blockers
a2-Agonists
CCBs
DA1 Agonists
Diuretics
Sympatholytics
Vasodilators
ANGIOTENSINOGEN
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Glu-Ser
•t-PA
•Cathepsin G
•Tonin
RENIN INHIBITORS
Renin
ANGIOTENSIN I
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
Angiotensin
Converting
Enzyme
•CAGE
ACE INHIBITORS
•Cathepsin G
•Chymase
ANGIOTENSIN II
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
AII ANTAGONISTS
AT1 Receptor
National Kidney Foundation Algorithm for
Achieving Target BP Goals in Hypertensive
Diabetic Patients
Blood pressure
>130/80 mm Hg
Baseline pulse 84
Add low-dose
beta blocker or
alpha/beta
blocker
Start ACE inhibitor
titrate upwards
BP still not
at goal
(130/80 mm Hg)
If BP still not
at goal
(130/80 mm Hg)
Add Thiazide
Diuretic or
long-acting CCB*
Baseline pulse <84
BP still not at goal
(130/80 mm Hg)
*If proteinuria present
(>300 mg per day)
non-DHP preferred.
If BP goal achieved, convert to fixed
dose combinations (ACE inhibitor +
CCB or ACE inhibitor + diuretic)
Add other subgroup of CCB
(ie, amlodipine-like agent if
verapamil or diltiazem already being
used and the converse)
Refer to a
clinical hypertension specialist
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
Treatment Targets for Diabetic
Renal Disease With Hypertension
Treatment Objectives to Prevent Macrovascular
Disease in Diabetic Patients
• Hypertension
– BP < 130/80 mmHg
• Hypercholesterolemia
– LDL < 100 mg/dL
• Hyperglycemia
– Hgb A1C < 7.0 %
American Diabetes Association Clinical Practice Recommendations.
Diabetes Care. 2001;24(suppl1):S1-S133.
National Kidney Foundation Recommendations on
Treatment of HTN and Diabetes
• Blood pressure goal: 130/80 mmHg
• Target blood pressure: 125/75 for patients
with >1 gram/day proteinuria
• Blood pressure lowering medications should
reduce both blood pressure + proteinuria
• Therapies that reduce both blood pressure
and proteinuria have been known to reduce
renal disease progression and incidence of
ischemic heart disease
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
Definitions of Microalbuminuria
and Macroalbuminuria
Parameter Normal
Microalbuminuria
Macroalbuminuria
Urine AER
(g/min)
< 20
20 - 200
>200
Urine AER
(mg/24h)
< 30
30 - 300
>300
Urine
albumin/
Cr# ratio
(mg/gm)
< 30
30 - 300
>300
AER=Albumin excretion rate
CR# =creatinine
Definitions of Diabetes Mellitus
• DIABETES MELLITUS
– Fasting (at least 8 hours) plasma glucose ≥126
mg/dL (7.0 mmol/L) on two or more different days
OR
– Random plasma glucose 200 mg/dL (must be
confirmed by fasting plasma glucose or oral glucose
tolerance test)
• IMPAIRED GLUCOSE TOLERANCE
– Oral glucose tolerance test yields fasting plasma
glucose <126 and 2 hr glucose levels 140-199
mg/dL
Source: www.diabetes.org
Management of
Chronic Renal Disease (CRD)
• New Definition of Renal Insufficiency
– Serum creatinine >1.4 mg/dL (men)
– Serum creatinine >1.2 mg/dL (women)
– Creatinine clearance <60 mL/min
• New Treatment Goal for Blood Pressure in
Patients with Renal Insufficiency
– Blood pressure <130/80 mmHg
Management of HTN and
Chronic Renal Disease (CRD)
• CRD Risk Factor Intervention
– Blood pressure
– Dyslipidemia
– Smoking
– Anemia
– Calcium and Phosphorus
Management of Risk Factors in HTN
and Chronic Renal Disease (CRD)
• Maximal reduction of proteinuria
– Dose titration of RAS inhibitors
– Therapeutic combinations
• Cardiovascular risk management
– Reduce CV risk factors
– Manage additional risk factors
•Anemia
•High plasma homocysteine
Management of HTN and Chronic
Renal Disease (CRD) in Diabetics
• Reduce BP to <130/80 mmHg
• Use multiple antihypertensive drugs (ACEI, ARB,
diuretic, CCB, beta-blocker)
• Maximal reduction of proteinuria
• Treat hyperlipidemia (LDL <100 mg/dL)
• Control Hgb A1C to <7%
• Modest dietary protein restriction (0.8-1.0 gm/kg
body weight/day)
• Low salt diet (<2 gm NaCl/day)
• Stop cigarette smoking
Management of Chronic
Renal Disease: Initial Diet Therapy
• For patients with modest renal insufficiency, reduce
intake of high biological quality protein* intake of 1
gm/kg body weight/day
• For patients with marked renal insufficiency, reduce
dietary protein intake to 0.8 gm/kg body weight/day
• Restrict dietary sodium intake to 4-6 gm/day
• Avoid foods rich in potassium
*high biological quality proteins are those rich in essential amino acids
Monitoring Patients With
Chronic Renal Disease
• Blood Pressure
• Creatinine clearance
– Serum creatinine
• Urinary Protein/Microalbuminuria
• Lipid Profile
• Glycemic Control
– Fasting blood glucose
– Post-prandial blood glucose
– HbA1C
Chronic Renal Disease:
Initial Treatment Recommendations
Renal Insufficiency
Clcr <60 mL/min
CrSerum >1.4 mg/dL*
130/80
Microalbuminuria
(only Abnormality)
130/80
Proteinuria
Diabetes Mellitus
*for women, CRSerum >1.2 mg/dL
ACE Inhibitor
(or ARB)
Start
And
Titrate
To Maximum
Tolerable
Dose
ACE Inhibition vs -Blockade on the
Progression of Renal Injury in Type 1 Diabetes
Blood Pressure
(mm Hg)
160
140
Decline in GFR
(mL/min)
0
120
100
Urinary Albumin
Excretion (g/24h)
2
Enalapril
-5
n=22
1.5
Metoprolol
80
40
20
0
0.5
-15
0 6 12 18 24 30 36
Time (months)
n=18
1
-10
60
0 6 12 18 24 30 36
Time (months)
Björck S, et al. BMJ. 1992;304(6823):339-343.
Reprinted by permission, BMJ Publishing Group.
0 6 12 18 24 30 36
Time (months)
Decline in GFR (mL/min/year)
A Greater Decline in Albuminuria Results
in Less Decline in GFR in Type 1 Diabetics
15
10
r=0.73
P<.001
5
0
-5
-100
-50
0
50
Relative change in albuminuria (%)
Rossing P, et al. Diabetologia. 1994;37(5):511-516.
©Springer-Verlag.
100
460
420
380
340
300
260
220
180
140
100
60
20
Placebo (n=45)
Enalapril
*
** *** ***
Percentage of initial
value 100/creatinine
Proteinuria (mg/24 h)
Long-Term Benefits of ACE Inhibition
in Normotensive Type 2 Diabetics
With Microalbuminuria
Enalapril (n=49)
110
105
100
*
95
*
90
85
†
†
Placebo
80
75
0
1
2
3
Years
4
5
0
1
*p<0.05; **p<0.01; †p<0.02; ***p<0.005
Ravid M, et al. Ann Intern Med. 1993;118(8):577-581.
Reprinted by permission, ACP-ASIM.
2 3
Years
4
5
Patients With CRD and HTN Have
Minimal Changes in Serum Creatinine
With ACEI or ARB Therapy
Serum Creatinine (mg/dL)
2.9
2.7
2.5
2.3
2.1
A
ACEI or
ARB
Started
B
1.9
1.7
1.5
1.3
1.1
0.9
0.7
C
Baseline
1
2
Weeks
Bakris GL, Weir M. Arch Intern Med. 2000;160(5):685-693.
Reprinted by permission, American Medical Association.
3
4
Hyperkalemia Crossover Trial:
ACE-I vs ARB Study Protocol
Randomization
Valsartan
Valsartan
Washout
Lisinopril
Time
-2
+
-1
0
*
Weeks
WASHOUT
PERIOD
Lisinopril
4
6
10
*
*
*
+BPx3,HRx3, A/C ratio x2, Calculated CrCl
*BPx3,HRx3, A/C ratio x2, GFR by Iohexol Procedure
Renin-AII-aldo (urine/serum),[K+](urine/serum) measured
Bakris GL, et al. Kidney Int. 2000;58(5):2084-2092.
Reprinted by permission, Blackwell Science, Inc.
Hyperkalemia Crossover Trial:
ACE-I vs ARB Results
Lisinopril (10 mg/d)
GFR < 60 mL/min/1.73m2
*
5
8 Lisinopril (10 mg/d)
4.9
7
Valsartan (80 mg/d)
4.8
Valsartan (80 mg/d)
6
pg/mL
4.7
4.6
4.5
5
*
4
4.4
3
4.3
4.2
Baseline
1 month
Baseline
Serum [K+]
2
1 month
Baseline 1 month Baseline 1 month
*P<0.05 from baseline.
Bakris GL, et al. Kidney Int. 2000;58(5):2084-2092.
Reprinted by permission, Blackwell Science, Inc.
Plasma Aldosterone
Escape of Angiotensin II
Despite ACE Inhibition
100
80
Plasma ACE
60
(nmoL/mL/min) 40
20
0
*
*
*
*
*
*
*
*
24 h
1
2
3
4
5
6
30
20
Plasma Ang II
(pg/mL)
10
*
0
Placebo
4h
Hospital
Months
*P <.001 vs placebo
Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4(6):966-972.
Crossover Study: Losartan vs ACE-I in
Non-Diabetic Patients w/ Proteinuria
20
% Change
10
0
-10
-20
-30
-40
-50
ERPF
*
*
N=11
*
*
GFR
*
BP
*
*
*
Uprot
*
*P<.05 vs baseline
4
*
8
*
*
*
12
16
20
24
Losartan Losartan Placebo Enalapril Enalapril Placebo
50 mg
100 mg Washout
10 mg
20 mg Washout
ERPF=effective renal plasma flow
GFR=glomerular filtration rate
Uprot=urinary protein excretion
Gansevoort RT, et al. Kidney Int. 1994;45(3):861-867.