epidemiology of renal disease in hypertension richard bright, m.d.f.r.s. 1789-1858 father of...

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


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


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.


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


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.


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

jgu

inan

/ap

c10

0/m

od

ule

s/U

rin

ary

/mam

mal/co

rtex1

/cort

ex.h

tml

trc.

ucd

avis

.ed

u/m

jgu

inan

/ap

c10

0/m

od

ule

s/U

rin

ary

/mam

mal/g

lom

eru

li0/g

lom

eru

li.h

tml

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•


O2•

TIMP

bFGF PDGF

Ang II

Proteases

(-)

(-)

(+)

(+)

(+)

TSP1

ET-1

PAI-1

O2•

TGF-


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


% 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


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


(up to 12 mos)


(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


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


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

* * * **

*

epidemiology of renal disease in hypertension richard bright, m.d.f.r.s. 1789-1858 father of...

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