epidemiology of renal disease in hypertension richard bright, m.d.f.r.s. 1789-1858 father of...
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Epidemiology ofEpidemiology ofRenal Disease inRenal Disease in
HypertensionHypertension
Richard Bright, M.D.F.R.S.1789-1858
Father of Nephrology
Renal Disease in HypertensionRenal Disease in HypertensionEpidemiologyEpidemiology
• 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 HypertensionRenal Disease in HypertensionA Historical PerspectiveA 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 Risk Factors for Progression of Renal DiseaseProgression 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 CauseESRD Due to Any CauseIn 332,544 Men Screened for MRFITIn 332,544 Men Screened for MRFIT
Adjusted Relative RiskAdjusted Relative Risk§§
1.0 1.2
22.1*
11.2*
6*
3.1*1.9*
0.0
5.0
10.0
15.0
20.0
25.0
Optimal Normal HighNormal
Stage 1 Stage 2 Stage 3 Stage 4
Blood Pressure Category
Adju
ste
d R
ela
tive R
isk
Hypertension
§ Men with optimal blood pressure was the reference category.
Klag MJ, et al. N Engl J Med. 1996;334(1):13-18.
* p<0.001
HTN Linked To Chronic Renal Disease Among HTN Linked To Chronic Renal Disease Among 332,544 Men Screened for MRFIT332,544 Men Screened for MRFIT
0
50
100
150
200
250
<8080-84
85-8990-99
100-109110
Ag
e-A
dju
ste
d R
ate
of
ES
RD
Per
100,0
00 P
ers
on
-Years
180 160-179 140-159 130-139 120-129 <120
Systolic BP (mm Hg) Diastolic
BP (m
m Hg)
Adapted from Klag MJ, et al. N Engl J Med. 1996;334(1):13-18.© Massachusetts Medical Society
Incidence Rates of Reported Incidence Rates of Reported ESRD by Primary DiagnosisESRD by Primary Diagnosis
0
40
80
120
160
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998
Incid
en
ce P
er
Millio
n
Po
pu
lati
on
Glomerulonephritis Hypertension Diabetes
YearUnited States Renal Data System (USRDS) 2000 Annual Data Report • WWW.USRDS.ORG
Diabetes50%
Hypertension27%
Glomerulonephritis13%
Other10%
Primary Diagnoses for Primary Diagnoses for Patients Who Start DialysisPatients Who Start Dialysis
United States Renal Data System (USRDS) 2000 Annual Data Report • WWW.USRDS.ORG
Persons Initiating Treatment for Persons Initiating Treatment for ESRD Related to Diabetes in the USESRD Related to Diabetes in the US
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
1984 1986 1988 1990 1992 1994 1996
Year
Nu
mb
er
of
Pe
op
le
CDC Diabetes Surveillance, 1997.
0
5
10
15
20
25
In M
illio
ns
1997 2010
Year
0
50
100
150
200
250
In M
illio
ns
1997 2010
Year
Amos A, McCarty D, Zimmet P. Diabetes Medicine. 1997;14[Suppl5]:S1-85.
Type I Diabetes Type II Diabetes
Global Estimates and ProjectionsGlobal Estimates and Projectionsfor Incidence of Diabetes Mellitusfor Incidence of Diabetes Mellitus
* p <0.0001
United States Renal Data System (USRDS) 2000 Annual Data Report • WWW.USRDS.ORG
Odds Ratio For ESRD By RaceRacial differences in ESRD in the USA from 1990 to 1998
1.00
4.45
3.57
1.59
0
1
2
3
4
5
White Black Native Asian
Od
ds
rati
o
reference
*
*
*
0
0.5
1
1.5
2
2.5
3
3.5
Ad
juste
d D
eath
Rate
(x
1000/y
ear)
Effect of Hypertension on Mortality Effect of Hypertension on Mortality in Diabetic Pima Indiansin Diabetic Pima Indians
Age-Adjusted Death Rates for Diabetic NephropathyAge-Adjusted Death Rates for Diabetic Nephropathy
Sievers ML, et al. Circulation. 1999;100(1):33-40.
NormotensiveDiabetics
N=10 deaths
HypertensiveDiabetics
N=75 deaths*p <0.001
*
Risk of Ischemic Heart Disease Risk of Ischemic Heart Disease Related to SBP and Related to SBP and MicroalbuminuriaMicroalbuminuria
0
1
2
3
4
5
6
SBP <140 SBP 140-160 SBP>160
Rela
tive R
isk Normoalbuminuria Microalbuminuria
Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
N=2,085; 10 year follow-up
0.5
1
1.5
2
2.5
3
Smok
ing
Micro
albu
min
uria
Mal
e Gen
der
Tota
l Cho
lest
erol
Syst
olic B
P
Rela
tive R
isk
Microalbuminuria Compared To Microalbuminuria Compared To Traditional Risk Factors For Ischemic Traditional Risk Factors For Ischemic
Heart DiseaseHeart Disease
N=2,085; 10 year follow-up
Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
A/C ra
tio >
0.6
5mg/
mm
ol
> 7
.0 m
mol/L
> 1
60 m
mHg
Crude Incidence Rates of Crude Incidence Rates of End Stage Renal Disease, By RaceEnd Stage Renal Disease, By Race
Racial differences in ESRD in the USA from 1990 to 1998Racial differences in ESRD in the USA from 1990 to 1998
0
200
400
600
800
1990 1991 1992 1993 1994 1995 1996 1997 1998
Year
Patie
nts p
er m
illion
pop
ula
tio
n
White Black Native Asian
United States Renal Data System (USRDS) 2000 Annual Data Report • WWW.USRDS.ORG
Comorbidities in Comorbidities in Renal Disease Patients (1999)Renal Disease Patients (1999)
0 20 40 60 80
Congestive heart failure
Ischemic heart disease
Myocardial infarction
Cardiac dysrhythmia
CVA/ TIA
Peripheral vascular
History of hypertension
Diabetes mellitus §
Diabetes on insulin ‡
COPD
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
Crude Incidence Rates of Crude Incidence Rates of Reported End Stage Renal DiseaseReported End Stage Renal Disease
0
100
200
300
400
1990 1992 1994 1996 1998
Year
Pati
ents
per
million
popula
tion
United States Renal Data System (USRDS) 2000 Annual Data Report • WWW.USRDS.ORG
Racial Distribution for Comorbidities Racial Distribution for Comorbidities In Dialysis Patients (1999)In Dialysis Patients (1999)
0
20
40
60
80
100
History ofHypertension
Diabetes§ CongestiveHeart Failure
Diabetes‡Insulin Treated
Perc
ent
of
Pati
ents
Black Asian Native White
§ 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
CV Mortality in General Population CV Mortality in General Population (GP) & Dialysis Patients, By Race (GP) & Dialysis Patients, By Race
0.001
0.010
0.100
1.000
10.000
100.000
25-34 35-44 45-54 55-64 65-74 75-84 85+
Age (years)
An
nu
al %
Mort
ality
(Log
Sca
le)
GP Black GP White
Dialysis Black Dialysis White
Sarnak MJ, Levey AS. Semin Dial. 1999;12:69-76.
Hypertension and Chronic Renal Disease: Hypertension and Chronic Renal Disease: Hemodynamic AbnormalitiesHemodynamic Abnormalities
Mean BPTotal Systemic
Vascular Resistance= X
Increased Cardiac Output Intravascular Volume Glomerular filtration Sodium excretion Extracellular Fluid Renal Nerve Activity Myocardial Performance Adrenergic Activity
Increased Cardiac Output Intravascular Volume Glomerular filtration Sodium excretion Extracellular Fluid Renal Nerve Activity Myocardial Performance Adrenergic Activity
IncreasedVasoconstriction Adrenergic Stimuli Angiotensin II Endothelin Endothelium-derived Contracting Factors Thromboxane
IncreasedVasoconstriction Adrenergic Stimuli Angiotensin II Endothelin Endothelium-derived Contracting Factors Thromboxane
CardiacOutput
DecreasedVasodilation Prostacyclin Nitric oxide EDHF*
DecreasedVasodilation Prostacyclin Nitric oxide EDHF*
Textor SC. Atlas of Diseases of the Kidney, 2001.
*Endothelium-derived Hyperpolarizing Factors
Prevalence of HypertensionPrevalence of HypertensionIn Chronic Renal DiseasesIn Chronic Renal Diseases
0
10
20
30
40
50
60
70
80
Hypert
ensio
n P
reva
lence (
%)
MCN CI N I gA MGN APKD DN MPGN FSGN
MCN=minimal change nephropathy CIN=chronic interstitial nephritis IgA=IgA nephropathyMGN=membranous glomerulonephritis APKD=adult-onset polycystic kidney disease DN=diabetic nephropathyMPGN=membranoproliferative glomerulonephritis FSGN=focal segmental glomerulonephritis
Smith MC and Dunn MJ, in Hypertension. Laragh JH, Brenner BM. Raven Press; 1995:2081-2101.
Hypertension and Hypertension and Renal Disease:Renal Disease:MechanismsMechanisms
Scanning electron (top) and light (bottom) micrographs of
a human glomerulus
trc.
ucd
avis
.ed
u/m
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tml
trc.
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u/m
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Glomerulus
Mesangial Matrix
Efferent Renal Arteriole
Mesangial Cells
Renal Sympathetic Nerves
Bowman’s Capsule
DistalConvoluted Tubule
Proximal Convoluted Tubule
Adventitial Mast Cell/Macrophage
Components of the Normal NephronComponents of the Normal Nephron
Vascular Smooth Muscle Cells
Juxtaglomerular Cells
Macula Densa
•Glomerular hypertension
•Hyperfiltration
•Glomerular barrier dysfunction
•Proteinuria
•Mesangial cell hyperplasia
•Intrarenal inflammatory processes
•Endothelial dysfunction
•VSMC proliferation
Normal KidneyNormal Kidney
Mechanisms of Renal Damage in HTNMechanisms of Renal Damage in HTN
Mechanisms
B l o o d P r e s s u r e
Functional
•Decrease in GFR
•Proteinuria
Structural
•Glomular basement membrane changes
•Expanded mesangial matrix
•Glomerulosclerosis
•Tubulo-interstitial fibrosisB l o o d P r e s s u r e
Consequences of Renal Damage in HTNConsequences of Renal Damage in HTN
Consequences
Renal FailureRenal Failure
Effects of Vasodilators Effects of Vasodilators in the Normal Kidneyin the Normal Kidney
L-ArginineNO
eNOS
(-)(-)
L-Citrulline
EDHF(s) Pgl2
(-) (-)
PMNM Platelet
(-)
VSMCEC
Imbalance in Factors Affecting Imbalance in Factors Affecting Vascular Tone and StructureVascular Tone and Structure
Nephron destruction and renal failure
Angiotensin II
Catecholamines
Endothelin-1
ROS
Cytokines
EDCF
Nitric Oxide
Prostacyclin
Bradykinin
EDHF
Constrictors/
Growth
PromotersDilators/
Growth
Inhibitors
Vascular tone and structure
EDHF= endothelium-derived hyperpolarizing factors
ROS= reactive oxygen species
EDCF= endothelium-derived constricting factors
+ = OONO_
(-)
ROS Reduces the ROS Reduces the Biological Effects of NOBiological Effects of NO
O2•
Afferent Arteriole
L-ArginineNO
eNOSL-Citrulline
NE
VSMC
PMNM
Fibroblast
EC
Mastcell
(+)
Renin-Angiotensin CascadeRenin-Angiotensin Cascade
Angiotensinogen
Angiotensin I
Angiotensin II
AT1AT2
ATn
Bradykinin
Inactivepeptides
Non-renin(eg tPA)
Non-ACE(eg chymase) ACE
Renin
Angiotensin II (Ang II) generated in the afferent arteriole interacts with AT1 receptors on cellular components of the nephron
Angiotensinogen Ang I
Renin
ACEAng II
AT1R
= AT1 Receptor
Role of Angiotensin II Role of Angiotensin II in Chronic Renal Diseasein Chronic Renal Disease
Adhesion molecules Chemotactic factors Cell growth Apoptosis TGF-, CTGF PAI-1
Glomerular capillarypressure
Single nephron GFR
Macrophageinfiltration
Angiotensin II
•Mechanical stress•Mesangial changes•Oxidative stress•Proteinuria•NF-B activation
Glomerulosclerosis
& Tubulo-interstitial
fibrosis
Renaldisease
Nephronloss
Adapted from Berk B. 2001.
Angiotensin II Induces Angiotensin II Induces Oxidative Stress in the KidneyOxidative Stress in the Kidney
• Stimulation of Membrane NOX-1 Oxidase*
– Increased superoxide (O2)
– Increased thiobarbituric acid reactive substances– Increased oxidized lipids– Increased tissue protein carbonyl content
• Induction of Heme Oxidase-1 (HO-1)• Activation of NF-B
– Increased inflammatory cytokines
*NAD(P)H Oxidase
O2 H2O2 H2O+O2O2•
Renal Sources of ROSRenal Sources of ROS
• NOX-1 oxidase*• Xanthine oxidase• Heme oxygenase–1• Cyclo-oxygenase• Lipoxygenase
• Cytochrome P450 mono-oxygenase
• Mitochondrial oxidative phosphorylation
*NADP(H) oxidase
Superoxidedismutase Catalase
O2 Endothelial Cells and
H2O2 Vascular Smooth Muscle
Oxidative Stress: Endothelial Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk FactorsDysfunction and CAD/Renal Risk Factors
Endothelial Dysfunction
Apoptosis
VasoconstrictionLeukocyteadhesion
Lipiddeposition
ThrombosisVSMCgrowth
HypertensionSmokingDiabetes LDL Homocysteine Estrogen
deficiency
Pivotal Role of ROS in Stimulus-Induced EC and Pivotal Role of ROS in Stimulus-Induced EC and VSMC Growth, Survival, and ApoptosisVSMC Growth, Survival, and Apoptosis
PDGF, Thrombin, Norepinephrine, Ang II, TNF, Ox-LDL, High Glucose, VEGF
ROS
Arachidonate Metabolism
Mitochondrial ElectronTransport Chain
CytochromeP450
NOX-1 Oxidase
Xanthine Oxidase
Growth or Hypertrophy
Survival Apoptosis
Caspases NF-B Akt ERKs JNKs
SAPKs
p38MAPK
Potential Targetsof ROS
Sources of ROS
Growth/DeathSurvival Signals
Pathologic Processes Leading to Pathologic Processes Leading to Glomerular Injury and ProteinuriaGlomerular Injury and Proteinuria
Ang II
Increasedglomerularpressure
Ang II
Urinary proteinGlucose
AGEs
Glycoxidation (glycation)
Efferent arteriolar
constriction
=angiotensin AT1 receptor
Vascular and/or Tubular Injury
Glomerular cells Tubular cellsLymphocytes Macrophages
Fibroblasts
TGF-ET-1CTGFAng IIPAI-1
PDGFbFGFTNF-IL-1
FIBROSIS
Fibrosis and Nephron Loss: Fibrosis and Nephron Loss: A Renal Response to InjuryA Renal Response to Injury
TGF-
TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron units
bFGF PDGF
Ang II
TSP1
TGF-
O2•
TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron units
O2•
TIMP
bFGF PDGF
Ang II
Proteases
(-)
(-)
(+)
(+)
(+)
TSP1
ET-1
PAI-1
O2•
TGF-
TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron units
O2•
Angiotensin II: Role in Renal InjuryAngiotensin II: Role in Renal Injury
Angiotensin II
AT1RAT2R
NF-B
TNFR1
TNFR2
Angiotensinogen
Fibroblasts
Proliferation and differentiation
Matrix
FIBROSIS
Inflammation
Cellular adhesion molecules
Tubule cells
TNF-
+ +
Profibrotic
cytokines
Aldosterone Promotes Renal FibrosisAldosterone Promotes Renal Fibrosisby Multiple Mechanismsby Multiple Mechanisms
Adrenal Vascular
AldosteronePAI-1
Nitric oxidesynthesis
Na+ influxinto VSMC
Norepinephrineuptake
into VSMC
Angiotensin II
AT1R bindingof Ang II
Stimulates Inhibits
Fibroblast collagen synthesis
Pathways Leading ToPathways Leading ToProgressive Renal FailureProgressive Renal Failure
Renal growth factor & cytokine
activation
Fibrogenesis
Systemic hypertension
Progressive Loss of Filtration Surface Area
GFR
Renal injury
Nephron mass
Glomerular hypertension
Renal scarring
Hyperlipidemia
Filtration of plasma proteins
(Proteinuria)
Proximal tubule protein uptake
Renal microvascular
injury
Influx of monocytes
and macrophages
Transdifferentiation of renal cells to
fibroblast phenotype
Brenner BM, Keane WF. 2001.
Clinical Trials in Clinical Trials in Hypertension and Hypertension and
Renal DiseasesRenal Diseases
Placebo + Other Antihypertensive Therapy
(excluding ACEI, AIIA)
Maintain prior antihypertensiv
e therapy (excluding ACEI,
AIIA)
Los 100 mg + Other Antihypertensive Therapy
(excluding ACEI, AIIA)
Los 100 mg
Goal BP< 140/90 mmHg
n = 1520
Los 50 mg
Placebo
NIDDM Patientswith proteinuria
Placebo
The Dual Significance of ProteinuriaThe 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 HypertensionRenal Disease and HypertensionCore Concepts of TreatmentCore 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 Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in Results in Slower Rates of Decline in GFR in Diabetics and Non-DiabeticsGFR in Diabetics and Non-Diabetics
9595 9898 101101 104104 107107 110110 113113 116116 119119
r = 0.69; P < 0.05
MAP (mmHg)
GF
R (
mL
/min
/yea
r)
130/85 140/90
UntreatedHTN
00
-2-2
-4-4
-6-6
-8-8
-10-10
-12-12
-14-14 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.Reprinted by permission, Harcourt Inc.
Meta Analysis: Lower Systolic BP Meta Analysis: Lower Systolic BP Results in Slower Rates of Decline in Results in Slower Rates of Decline in GFR in Diabetics and Non-DiabeticsGFR in Diabetics and Non-Diabetics
130 134 138 142 146 150 154 170 180
r = 0.69; P < .05
SBP (mmHg)
GF
R (
mL
/min
/yea
r)
UntreatedHTN
0
-2
-4
-6
-8
-10
-12
-14
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
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.
Goal BP Recommendations for Goal BP Recommendations for Patients with DM or Renal DiseasePatients with DM or Renal Disease
Organization Year Systolic
BPDiastolic
BPAmerican Diabetes Association 2001 <130 <80
National Kidney Foundation 2000 <130 <80
Canadian Hypertension Society 1999 <130 <80
British Hypertension Society 1999 <140 <80WHO & International
Society of Hypertension1999 <130 <85
Joint National Committee (JNC VI)
1997 <130 <85
JNC-VI General Goals for BP ControlJNC-VI General Goals for BP Control
Pre-existing condition
% achievedBP 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 Frequency of Proteinuria (Albuminuria) in the United States(Albuminuria) in the United States
Adults With Proteinuria
QuantitationTotal adults(in millions)
% of adultsin US
Increased urine ratioalbumin/creatinine
(>30 mg/gm)
20.2 11.7
Proteinuria(>300mg/24h)
18.3 10.6
Microalbuminuria(30-300 mg/24h)
1.9 1.1
Keane WF, Eknoyan G. Am J Kidney Dis. 1999;33(5):1004-1010
Impact of Blood Pressure Reduction Impact of Blood Pressure Reduction on Mortality in Diabeteson Mortality in Diabetes
TrialConventiona
lcare
Intensivecare
Risk reduction
P-value
UKPDS
154/87 144/82 32% 0.019
HOT 144/85 140/81 66% 0.016
Turner RC, et al. BMJ. 1998;317:703-713. Hansson L, et al. Lancet. 1998;351:1755–1762.
Mortality endpoints are:UK Prospective Diabetes Study (UKPDS) – “diabetes related deaths”Hypertension Optimal Treatment (HOT) Study – “cardiovascular deaths” in diabetics
UK Prospective Diabetes Study (UKPDS) UK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk ReductionsMajor 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 Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDSControl and CV Outcomes in UKPDS
StrokeAny Diabetic
EndpointDM
DeathsMicrovascularComplications
-50
-40
-30
-20
-10
0
% R
ed
ucti
on
In
Rela
tive R
isk
Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL)
Tight BP Control (Average 144/82 mmHg)
32%
37%
10%
32%
12%
24%
5%
44%
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.Reprinted by permission, Harcourt Inc.
*
*
**
*P <0.05 compared to tight glucose control
17% decrease per 10 mmHg decrement in BP
p<0.0001
0.5
1
5
110 120 130 140 150 160 170
UKPDS: Relationship Between BP Control UKPDS: Relationship Between BP Control And Diabetes-Related DeathsAnd Diabetes-Related Deaths
Mean systolic blood pressure (mmHg)
Haza
rd r
ati
o
Adler AI, et al. BMJ. 2000;321:412-419.Reprinted by permission, BMJ Publishing Group.
HOT Trial: BP Control Reduces HOT Trial: BP Control Reduces Cardiovascular Events in DiabeticsCardiovascular Events in Diabetics
Hansson L, et al. Lancet. 1998;351:1755–1762.
Maj
or
CV
eve
nts
*10
00 p
atie
nt-
yrs
30
25
20
15
10
5
0
P < .005
24.4
18.6
11.9
*includes all myocardial infarction, all strokes, and all other CV deaths
Diabetes SubgroupTarget
Diastolic BP
(mmHg)
Number of Patients
Achieved†
SystolicBP
(mmHg)
Achieved†
DiastolicBP
(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
Landmark ACE Inhibitor Landmark ACE Inhibitor Trials in DiabeticsTrials in Diabetics
Study Drug N DosingStudy years
Endpoint P-value
Lewis Captopril 409 25 mg tid ~ 3Doubling of
serum creatinine
P=0.007
Lebovitz Enalapril 1655-40 mg qd
~ 3Correlation of MAP w/ rate of change in GFR
P=0.026
ABCD Trial
Enalapril 4705-40 mg qd
524-hr creatinine
clearanceNS
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.
ABCD = Appropriate Blood Pressure Control in Diabetes Trial
ACE-I Is More Renoprotective Than ACE-I Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes Conventional Therapy in Type 1 Diabetes
% with doubling of
baseline creatinine
100
75
50
25
00 1 2 3 4
Baseline creatinine >1.5 mg/dL
Captopriln=207
Placebon=202
P<.001
Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.
Years of follow-up
ACE-I Is More Renoprotective than ACE-I Is More Renoprotective than Conventional Therapy in Type 1 Diabetes Conventional Therapy in Type 1 Diabetes
% c
han
ge in
pro
tein
uri
a
40
20
0
-20
-40
-60CaptoprilPlacebo
P<.001
Decr
ease
in
mean
art
eri
al
pre
ssu
re (
mm
Hg
)
2
0
2
-4
-6
-8CaptoprilPlacebo
NS
Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.
Relationship of Achieved Mean Arterial Relationship of Achieved Mean Arterial Pressure to Parameters of Renal Function Pressure to Parameters of Renal Function
in Type 1 Diabetesin Type 1 DiabetesMean
arterialpressure(mmHg)*
nFinal total
proteinuria(mg/24h)
Serumcreatinin
e(mg/dL)
GFR(mL/min)
# patients with final
proteinuria <500 mg/24h
< 92 47 1,073 + 1,535† (418) +0.14† -5.2† 27
92.1–99.9 41 1,830 + 1,701 (1,798) +0.38 -6.2 11
100–107 32 4,249 + 4,754 (2,659) +0.38 -11.6 2
107.1 6 4,882 + 2,878 (5,825) +0.92 -11.0 0
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.
125
140
155
170
Baseline 1 Month 5.6 Yrs Month offACE-I
+Clonidine
SB
P (
mm
Hg
)Impact of ACE-I on BP and GFR:Impact of ACE-I on BP and GFR:
Acute and Chronic EffectsAcute and Chronic Effects
60
65
70
75
80
85
90
Baseline 1 Month 5.6 Yrs Month offACE-I
+Clonidine
*P<0.05 compared to baseline
Bakris GL, Weir MR. Arch Intern Med. 2000;160(5):685-93.©American Medical Association
GFR
ml/m
in/1
.73m
2
** *
**
ARB (Losartan) Reduces Urinary Albumin and ARB (Losartan) Reduces Urinary Albumin and TGF-TGF-1 in Type 2 Diabetes with Microalbuminuria1 in Type 2 Diabetes with Microalbuminuria
Esmatjes E, et al. Nephrol Dial Transplant. 2001;16(Suppl1):90-93.
160
140
130
120
24-hour Systolic BPP<0.01 vs baseline
mm
Hg
4 Weeks
90
80
70
60
24-hour Diastolic BPP<0.03 vs baseline
Baseline 8 Weeks
mm
Hg
50
Urinary Albumin ExcretionP<0.01 vs baseline
100
90
80
70
60
mcg
/min
6
5
4
3
2 1
TGF-P<0.005 vs baseline
Baseline 4 Weeks 8 Weeks
ng
/mL
Landmark Trials in Diabetics and Non-Diabetics Landmark Trials in Diabetics and Non-Diabetics with ESRD/Death as an Endpointwith ESRD/Death as an Endpoint
Trial YearEndpoint
significanceAchieved 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 inLandmark Renal Trials inNon-Diabetics with ACE InhibitorsNon-Diabetics with ACE Inhibitors
Study Drug DosingSurvival Benefit
Study Duration
AIPRI Benazepril 10-20mg 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 StudyREIN = 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 AIPRI: Baseline Prognostic Factors and Reduction of Risk for Progressive Renal Insufficiency with ACE-IRisk for Progressive Renal Insufficiency with ACE-I
≤1gm >1 to <3gm ≥3gm
24-Hr Urine Protein Excretion
-80
-70
-60
-50
-40
-30
-20
-10
0
% r
isk
re
du
cti
on
>45 ml/min ≤45 ml/min
Creatinine Clearance
71%
46%
31%
53%
66%
Maschio G, et al. N Engl J Med. 1996;334(15):939-945.
REIN Study: ACE Inhibition in Proteinuric REIN Study: ACE Inhibition in Proteinuric Non-Diabetic NephropathyNon-Diabetic Nephropathy
Baseline SBP ∆ SBPBaseline
DBP∆ DBP
Ramipril
149.8 -5.8 mmHg 92.4 -4.2 mmHg
Placebo 148.0 -3.4 mmHg 91.3 -3.4 mmHg
00 66 1212 1818 2424 3030 3636
100
80
60
40
20
0
100
80
60
40
20
0
RamiprilRamipril
PlaceboPlacebo
P=0.02P=0.02
The GISEN Group. Lancet. 1997;349:1857–1863.
% o
f pati
ents
wit
hout
com
bin
ed e
ndp
oin
t*
*Combined endpoint = doubling of baseline serum creatinine concentration or end stage renal failure
REIN Study: ACE Inhibition in Proteinuric REIN Study: ACE Inhibition in Proteinuric Non-Diabetic NephropathyNon-Diabetic Nephropathy
Mea
n r
ate
of
GF
R d
ecli
ne
(mL
/min
/mo
nth
)
1.61.41.21.00.80.60.40.20.0
Baseline urinary protein excretion
(g/24 h)
n = 613–4.5
n = 364.5–7.0
n = 20 7.0
The GISEN Group. Lancet. 1997;349:1857–1863.
% p
ts w
ith
do
ub
lin
go
f b
asel
ine
Cr
or
ES
RD 70
60
50
40
30
20
10
0
Baseline urinary protein excretion
(g/24 h)
n = 873–4.5
n = 484.5–7.0
n = 31 7.0
Placebo
Ramipril
REIN Study: Ramipril Group Median REIN Study: Ramipril Group Median Change in Urinary Protein ExcretionChange in Urinary Protein Excretion
-60
-50
-40
-30
-20
-10
0
0 1 3 6 12 24 36
% c
han
ge in
uri
nary
p
rote
in e
xcre
tion
Months
The GISEN Group. Lancet. 1997;349:1857–1863.
ACE-I Provides Greater Renoprotection ACE-I Provides Greater Renoprotection Than Non-ACE-I in Patients with Than Non-ACE-I in Patients with
Diabetic and Non-Diabetic NephropathyDiabetic and Non-Diabetic Nephropathy
Study YearConclusions about
ACE inhibitors (ACE-I)
Bjork et al 1992 ACE-I reduced both the rate of decline in GFR and the amount of albuminuria.
Lewis et al 1993In Type I diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced.
REIN 1997In non-diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced.
MicroHOPE 2000ACE-I reduced progression of proteinuria from normoalbuminuria to microalbuminuria and from microalbuminuria to macroalbuminuria.
AASK 2001ACE-I was superior to amlodipine in reducing proteinuria among non-diabetic African Americans with hypertension and kidney disease.
AASK: The African American Study AASK: The African American Study of Kidney Disease and Hypertensionof 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:HOPE TRIAL:Independent Predictive Variables for Combined Independent Predictive Variables for Combined
Endpoints of CV Death, MI, and StrokeEndpoints of CV Death, MI, and Stroke
Variable Hazard Ratio
Microalbuminuria 1.59
Creatinine > 1.4 mg/dL 1.40
CAD 1.51
PVD 1.49Diabetes Mellitus 1.42
Male 1.20Age 1.03
Waist-Hip Ratio 1.13
Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.
0
10
20
30
40
0
10
20
30
40
50
60
0
10
20
30
40
50
60
0
20
40
60
80
<1.4 mg/dL
All Patients Placebo
Even
ts p
er
1000 P
ers
on
-Years
, n Primary
Outcome*Myocardial Infarction*
CardiovascularDeath*
All Death*
>1.4 mg/dL <1.4 mg/dL >1.4 mg/dL
<1.4 mg/dL >1.4 mg/dL<1.4 mg/dL >1.4 mg/dL
Ramipril
HOPE Trial: HOPE Trial: Main Outcomes and Serum CreatinineMain Outcomes and Serum Creatinine
Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.Reprinted by permission, ACP-ASIM.
*p=<0.001
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
<1.4 mg/dL
Placebo Ramipril
Even
ts p
er
1000 P
ers
on
-Years
, n
DiabeticPatients
Hypertensive Patients
Non-Diabetic Patients Normotensive Patients
>1.4 mg/dL <1.4 mg/dL >1.4 mg/dL
<1.4 mg/dL >1.4 mg/dL<1.4 mg/dL >1.4 mg/dL
HOPE Trial: HOPE Trial: Primary Outcomes and Serum CreatininePrimary Outcomes and Serum Creatinine
Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.Reprinted by permission, ACP-ASIM.
Comparison of Anti-Hypertensive Comparison of Anti-Hypertensive Regimens on Proteinuria 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 Changes in Albuminuria and Mean Arterial Pressure (MAP) in Studies Mean Arterial Pressure (MAP) in Studies
of Patients with HTN and Proteinuriaof Patients with HTN and Proteinuria
-50
-40
-30
-20
-10
0
10
20
Pe
rce
nt
Ch
an
ge
MAP(mmHg) Albuminuria
N=173 N=121 N=111 N=723
Nifedipine
OtherDihydropyridine
CCBs
Diltiazem &Verapamil
CCBsAll
ACE Inhibitors
Kloke H, et al. Kidney Int. 1998;53:1559-1573.
ACE-I + Verapamil: Additive Reduction of ACE-I + Verapamil: Additive Reduction of Proteinuria in Type 2 Diabetes at 1 YearProteinuria in Type 2 Diabetes at 1 Year
Trandolapril (5.5 mg/d)
Verapamil (315 mg/d)
Trandolapril (2.9 mg/d) + Verapamil (219 mg/d)
-70
-60
-50
-40
-30
-20
-10
0
MAP Proteinuria
*
Bakris GL, et al. Kidney Int. 1998;54:1283-1289. Reprinted by permission, Blackwell Science, Inc.
-33%
-27%
-62%
*p <0.001 combination vs either monotherapy
Perc
en
t re
du
cti
on
n=12 n=11 n=14
Therapeutics in Therapeutics in Hypertension and Hypertension and Renal DiseasesRenal Diseases
Renal Diseases in HypertensionRenal Diseases in HypertensionCore Concepts of TreatmentCore Concepts of Treatment
• Hypertension is an independent variable that predicts long-term decline in renal function
• Proteinuria is also an independent variable that predicts long-term 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-VIRisk Stratification: JNC-VIRisk 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
BP Stages
Systolic BP
(mmHg)
Diastolic BP
(mmHg)
High Normal
130-139
85-89 Lifestyle modification
Lifestyle modification
Drug therapy§
Stage 1140-159
90-99
Lifestyle modification
(up to 12 mos)
Lifestyle modification
(up to 6 mos)
Drug therapy
Stage 2 & 3 > 160 > 100 Drug
therapyDrug
therapyDrug 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 JNC-VI Treatment Recommendations for High Risk Hypertensivesfor High Risk Hypertensives
Risk Group C•Diabetes…and/or•TOD & CCD Other risk factors
BP Stage Systolic BP(mmHg)
Diastolic BP(mmHg)
High Normal 130-139 85-89 Drug therapy§
Stage 1 140-159 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 WHO-ISH 1999 Guidelines for Management of HTN: CV Risk and Prognosisof HTN: CV Risk and Prognosis
Riskstrata
Other risk factors & disease history
Systolic and Diastolic BP (mmHg)
Grade 1Mild HTN
SBP 140-159 or DBP 90-99
Grade 2Moderate HTNSBP 160-179
or DBP 100-109
Grade 3Severe HTNSBP 180
or DBP 100
INo other risk
factors Low risk Medium risk High risk
II 1-2 risk factors Medium risk Medium riskVery high
risk
III 3 risk factors or
TOD or DM High risk High riskVery high
risk
IVAssociated
clinical conditionsVery high
riskVery high
riskVery high
risk
WHO-ISH Guidelines. J Hypertens. 1999;17(2):151-183.©Lippincott, Williams & Wilkins • www.lww.com
TOD=Target Organ Damage/Associated Clinical Conditions include clinical cardiovasular disease or renal disease
Treatment of Treatment of High Risk HypertensivesHigh Risk Hypertensives
Patient typeBP 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 Average Number of Anti-Hypertensive Agents Used to Achieve Target BPAgents Used to Achieve Target BP
MDRD ABCD HOT UKPDS
Goal BP<92 mmHg
MAP*
<75 mmHgDBP
<80 mmHgDBP
<85 mmHgDBP
Achieved BP
93 ~75 81 82
Avg # of drugs per patient
3.6 2.7 3.3 2.8
*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 Physician Practices in Treating HTN With and Without DiabetesHTN With and Without Diabetes
0
10
20
30
40
50
60
80-84 85-89 90-94 95-99 100-110
40-60y/no DM >70y/no DM40-60y/with DM >70y/with DM
Hyman DJ, Pavlik VN. Arch Intern Med. 2000;160(15):2281-2286.Reprinted by permission, American Medical Association.
DBP (mmHg) to Start Treatment
% o
f re
sp
on
den
ts
Anti-Hypertensive Drugs: Anti-Hypertensive Drugs: Sites of ActionSites of Action
-Blockers
CCBs*
Diuretics
ACE Inhibitors AT1 Blockersa-Blockersa2-Agonists
CCBsDA1 Agonists
DiureticsSympatholytics
Vasodilators
Blood Pressure
Cardiac Output
Total Peripheral Resistance
= X
* = non-dihydropyridine CCBs
ANGIOTENSIN I
ANGIOTENSIN II
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Glu-Ser
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
Angiotensin Converting
Enzyme
Renin
AT1 Receptor
RENIN INHIBITORS
ACE INHIBITORS
AII ANTAGONISTS
ANGIOTENSINOGEN
•t-PA
•Cathepsin G
•Tonin
•CAGE
•Cathepsin G
•Chymase
Start ACE inhibitor titrate upwards
Start ACE inhibitor titrate upwards
If BP still not at goal
(130/80 mm Hg)
If BP still not at goal
(130/80 mm Hg)
BP still not at goal
(130/80 mm Hg)
Baseline pulse <84Baseline pulse <84
Add low-dose beta blocker or
alpha/beta blocker
Add low-dose beta blocker or
alpha/beta blocker
Add other subgroup of CCB(ie, amlodipine-like agent if
verapamil or diltiazem already being used and the converse)
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
BP still not at goal (130/80 mm Hg)
If BP goal achieved, convert to fixed dose combinations (ACE inhibitor +
CCB or ACE inhibitor + diuretic)
Baseline pulse 84Baseline pulse 84Add Thiazide Diuretic or
long-acting CCB*
Add Thiazide Diuretic or
long-acting CCB*
Blood pressure >130/80 mm HgBlood pressure >130/80 mm Hg
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
National Kidney Foundation Algorithm for National Kidney Foundation Algorithm for Achieving Target BP Goals in Hypertensive Achieving Target BP Goals in Hypertensive
Diabetic PatientsDiabetic Patients
*If proteinuria present (>300 mg per day) non-DHP preferred.
Treatment Targets for Diabetic Treatment Targets for Diabetic Renal Disease With HypertensionRenal Disease With Hypertension
Treatment Objectives to Prevent Macrovascular Treatment Objectives to Prevent Macrovascular Disease in Diabetic PatientsDisease 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 National Kidney Foundation Recommendations on on
Treatment of HTN and DiabetesTreatment 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 Definitions of Microalbuminuria and Macroalbuminuriaand Macroalbuminuria
Parameter NormalMicro-
albuminuriaMacro-
albuminuria
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 MellitusDefinitions of Diabetes Mellitus
• DIABETES MELLITUS– Fasting (at least 8 hours) plasma glucose ≥126
mg/dL (7.0 mmol/L) on two or more different daysOR
– 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 Management of Chronic Renal Disease (CRD)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 Management of HTN and Chronic Renal Disease (CRD)Chronic Renal Disease (CRD)
• CRD Risk Factor Intervention– Blood pressure– Dyslipidemia– Smoking– Anemia– Calcium and Phosphorus
Management of Risk Factors in HTN Management of Risk Factors in HTN and Chronic Renal Disease (CRD)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 Management of HTN and Chronic Renal Disease (CRD) in DiabeticsRenal 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 Management of Chronic Renal Disease: Initial Diet TherapyRenal 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 Monitoring Patients With Chronic Renal DiseaseChronic 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:Chronic Renal Disease:Initial Treatment RecommendationsInitial Treatment Recommendations
Renal InsufficiencyClcr <60 mL/min
CrSerum >1.4 mg/dL*
Renal InsufficiencyClcr <60 mL/min
CrSerum >1.4 mg/dL*
Microalbuminuria(only Abnormality)Microalbuminuria(only Abnormality)
Diabetes MellitusDiabetes Mellitus
ACE Inhibitor(or ARB)
StartAnd
Titrate To Maximum
TolerableDose
ACE Inhibitor(or ARB)
StartAnd
Titrate To Maximum
TolerableDose
130/80130/80
130/80130/80
ProteinuriaProteinuria
*for women, CRSerum >1.2 mg/dL
ACE Inhibition vs ACE Inhibition vs -Blockade on the -Blockade on the Progression of Renal Injury in Type 1 DiabetesProgression of Renal Injury in Type 1 Diabetes
Decline in GFR(mL/min)
Time (months)
0
-5
-10
-15
Time (months)
0 6 12 18 24 30 36
2
1.5
1
0.5
Urinary Albumin Excretion (g/24h)
Björck S, et al. BMJ. 1992;304(6823):339-343.Reprinted by permission, BMJ Publishing Group.
Blood Pressure(mm Hg)
Time (months)
160
120
80
60
140
100
40200
Enalapriln=22
Metoprololn=18
0 6 12 18 24 30 360 6 12 18 24 30 36
A Greater Decline in Albuminuria Results A Greater Decline in Albuminuria Results in Less Decline in GFR in Type 1 Diabeticsin Less Decline in GFR in Type 1 Diabetics
15
10
5
0
-5-100 -50 0 50 100
Relative change in albuminuria (%)
Decl
ine in G
FR (
mL/
min
/year)
Rossing P, et al. Diabetologia. 1994;37(5):511-516.©Springer-Verlag.
r=0.73 P<.001
Pro
tein
uri
a (
mg
/24
h)
Years
460420380340300260220180140100
6020
0 1 2 3 4 5
Placebo (n=45)
Enalapril
Perc
en
tag
e o
f in
itia
l valu
e 1
00
/cre
ati
nin
eYears
0 1 2 3 4 5
110
105
100
95
90
85
80
75
Placebo
Enalapril (n=49)
Ravid M, et al. Ann Intern Med. 1993;118(8):577-581.Reprinted by permission, ACP-ASIM.
Long-Term Benefits of ACE Inhibition Long-Term Benefits of ACE Inhibition in Normotensive Type 2 Diabetics in Normotensive Type 2 Diabetics
With MicroalbuminuriaWith Microalbuminuria
* ** *** ***
** †
†
*p<0.05; **p<0.01; †p<0.02; ***p<0.005
WeeksWeeks
2.9
2.7
2.5
2.3
2.1
1.9
1.7
1.5
1.3
1.1
0.9
0.7
2.9
2.7
2.5
2.3
2.1
1.9
1.7
1.5
1.3
1.1
0.9
0.7
Seru
m C
reati
nin
e (
mg
/dL)
Seru
m C
reati
nin
e (
mg
/dL)
BaselineBaseline 11 22 33 44
AA
BB
CC
ACEI or ARB
Started
ACEI or ARB
Started
Bakris GL, Weir M. Arch Intern Med. 2000;160(5):685-693.Reprinted by permission, American Medical Association.
Patients With CRD and HTN Have Patients With CRD and HTN Have Minimal Changes in Serum Creatinine Minimal Changes in Serum Creatinine
With ACEI or ARB TherapyWith ACEI or ARB Therapy
Hyperkalemia Crossover Trial: Hyperkalemia Crossover Trial: ACE-I vs ARB Study ProtocolACE-I vs ARB Study Protocol
Washout
Randomization
Lisinopril
* *+BPx3,HRx3, A/C ratio x2, Calculated CrCl*BPx3,HRx3, A/C ratio x2, GFR by Iohexol ProcedureRenin-AII-aldo (urine/serum),[K+](urine/serum) measured
* *
Valsartan Valsartan
Lisinopril
Weeks
Time
-2 0 4 6 10
WASHOUTPERIOD
-1
+
Bakris GL, et al. Kidney Int. 2000;58(5):2084-2092.Reprinted by permission, Blackwell Science, Inc.
Hyperkalemia Crossover Trial: Hyperkalemia Crossover Trial: ACE-I vs ARB ResultsACE-I vs ARB Results
*P<0.05 from baseline.
GFR < 60 mL/min/1.73m2
Bakris GL, et al. Kidney Int. 2000;58(5):2084-2092.Reprinted by permission, Blackwell Science, Inc.
2
3
4
5
6
7
8
Plasma Aldosterone
*pg/m
L
Lisinopril (10 mg/d)
Baseline Baseline1 month 1 month
Valsartan (80 mg/d)
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
5 *
mEq/ L
Baseline
Lisinopril (10 mg/d)
Serum [K+]
Baseline1 month 1 month
Valsartan (80 mg/d)
Escape of Angiotensin II Escape of Angiotensin II Despite ACE Inhibition Despite ACE Inhibition
Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4(6):966-972.
Plasma Ang II(pg/mL)
Plasma ACE(nmoL/mL/min)
*
********
0
10
20
30
Placebo 4 h 24 h 1 2 3 4 5 6
Hospital Months
020406080
100
*P <.001 vs placebo
Crossover Study: Losartan vs ACE-I in Crossover Study: Losartan vs ACE-I in Non-Diabetic Patients w/ ProteinuriaNon-Diabetic Patients w/ Proteinuria
20
10
0
-10
-20
-30
-40
-50
4 8 12 16 20 24
ERPF=effective renal plasma flow GFR=glomerular filtration rate Uprot=urinary protein excretion
Losartan50 mg
Losartan100 mg
PlaceboWashout
Enalapril10 mg
Enalapril20 mg
PlaceboWashout
* * * *
* * *
ERPF
GFR
BP
Uprot
% C
hange
Gansevoort RT, et al. Kidney Int. 1994;45(3):861-867.
N=11
*P<.05 vs baseline
* * * **
*
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