Hypertension in ESRD Hypertension in ESRD Lancet; 2002; 360:1903 - - PowerPoint PPT Presentation

Hypertension in ESRD Hypertension in ESRD

Carmine Zoccali Carmine Zoccali

Lancet; 2002; 360:1903

Usual systolic BP

mmHg

Ischemic Heart Disease Mortality

4th 5th 6th 7th 8th

low risk populations low risk populations

This specification is This specification is important because the important because the association can be association can be used to predict risk used to predict risk

• nly in populations
• nly in populations

having the same risk having the same risk profile. profile.

0.65 0.65 1.52 1.52 2.31 2.31

80 80 100 120 140 160 180 100 120 140 160 180 Systolic BP Systolic BP (mmHg)

(mmHg)

Drawn from data reported in the study Drawn from data reported in the study

4 year 4 year

Cardiac death Cardiac death RR RR 2.0 2.0 1.5 1.5 1.0 1.0 0.5 0.5 0.0 0.0

Rotterdam Heart Study Rotterdam Heart Study

Paradoxical? Paradoxical?

• .This is what we expect in

.This is what we expect in patients with pump failure patients with pump failure

• .high risk populations

.high risk populations a different story.. a different story.. Prognostic models apply Prognostic models apply just to the population just to the population whereupon they were whereupon they were derived .. derived ..

Individuals without CV Individuals without CV complications to start with complications to start with

Risk Risk BP BP

Patients with HF and Patients with HF and high risk patients in high risk patients in general general

Mixed Populations

• Syst. BP
• Syst. BP

20 20

• 20

20

• 40

40 <120 <120

Pre Pre-

• dialysis Systolic

dialysis Systolic (mmHg (mmHg)

) Survivors >1year Survivors >1year Non Non-

• survivors

survivors

48:606 48:606-

• 615. 2006
• 615. 2006

HR HR

6 6 4 4 2 2 1 1 <120 <140 <160 <180 <200 <120 <140 <160 <180 <200 > >200 200 Pre Pre-

• dialysis Systolic

dialysis Systolic

These data are clearly in These data are clearly in line with the hypothesis that line with the hypothesis that the link between low BP and the link between low BP and ⇑ ⇑ risk of death is an risk of death is an epiphenomenon of epiphenomenon of deterioration pump function deterioration pump function 56.000 incident dialysis patients, Fresenius MC 56.000 incident dialysis patients, Fresenius MC

Basic mechanism(s) of hypertension in ESRD Basic mechanism(s) of hypertension in ESRD Therapy Therapy

Prevalence % 100 80 60 40 20

CKD

120 80 40

GFR ml.min.1.73m2 90%

ESRD

Risk Reduction Risk Reduction for Death or for Death or ⇑ ⇑ LVMI LVMI %

• 10
• 20
• 30
• 40

100 80 60 40 20 Prevalence %

CKD

120 80 40

GFR ml.min.1.73m2

Centers applying a policy based on long/frequent dialysis and low salt intake Short dialysis, no surveillance of salt intake

90% Systolic BP Systolic BP mmHg

mmHg 170 170 160 160 150 150 140 140 130 130 120 120

Baseline 1 Baseline 1-

• year

year

E-pub, ahead of print, 20° Nov 2010

Conventional Frequent

ESRD

• 39%

0 or 0 ability to excrete Na VOLUME expansion

⇓ restraint of central sympathetic activity

ESRD

Sympathetic fibers, Sympathetic fibers, peroneal nerve peroneal nerve

High sympathetic activity

afferent nerves

ESRD

Sympathetic fibers, Sympathetic fibers, peroneal nerve peroneal nerve

High sympathetic activity

327:1912-18, 1992

Bursts/min Bursts/min

60 60 40 40 20 20

Healthy Healthy subjects subjects HD HD patients patients HD HD Patients Patients Post Post-

• nephrectomy

nephrectomy

MAP MAP

mmHg mmHg 100 100 90 90 80 80 70 70 60 60 ⇓ restraint of central sympathetic activity

0 or 0 ability to excrete Na VOLUME expansion

VOLUME expansion has indirect influences on sympathetic activity

ESRD

⇓ restraint of central sympathetic activity

0 or 0 ability to excrete Na VOLUME expansion

Nocturnal Nocturnal hypoxemia hypoxemia

Sleep Sleep Apnea Apnea

⇑⇑ sympathetic activity

Volume Expansion, sleep apnea (nocturnal hypoxemia) and Sympathetic Overactivity are among the most solidly established factors underlying Hypertension in ESRD

RENALASE

⇓⇓ ⇓⇓ RENALASE RENALASE (monoaminoxidase) (monoaminoxidase) ⇓⇓ ⇓⇓ ability to degrade ability to degrade catecholamins catecholamins

Airways narrowing Airways narrowing due to due to pharingeal pharingeal edema edema and and recumbency recumbency

0 16.7 33.3 50.0 0 16.7 33.3 50.0 time (months) time (months)

1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 Fatal and non Fatal and non-

• fatal CV events

fatal CV events non hypoxemic (SO non hypoxemic (SO2

2 >95%)

>95%) hypoxemic (SO hypoxemic (SO2

2 <95%)

<95%)

Also beyond BP, nocturnal hypoxia is a strong risk factor in Also beyond BP, nocturnal hypoxia is a strong risk factor in ESRD ESRD

• Zoccali C et al J Am Soc Nephrol. 2002;13:729-33.

Independent of BP and Independent of BP and

• ther risk factors
• ther risk factors

• .independently of BP, high sympathetic activity is a strong

.independently of BP, high sympathetic activity is a strong predictor of CV events in ESRD predictor of CV events in ESRD

CV Death (%) CV Death (%) 60 60 40 40 20 20

Zoccali C et al., Circulation 105: 1354, 2002 Zoccali C et al., Circulation 105: 1354, 2002

0 10 20 30 40 50 55 0 10 20 30 40 50 55 months months Nor Nor-

• Epi < median value

Epi < median value Nor Nor-

• Epi > median value

Epi > median value

Basic mechanism(s) of hypertension in ESRD Basic mechanism(s) of hypertension in ESRD Therapy Therapy

HR

2.0 1.5 1.0 0.5 0.0 First Second Third <138 139-155 >155 mmHg

All cause mortality CV mortality Stroke mortality

Dialysis patients in the seventies were a selected, relatively young population (diabetics and those with CV complications often excluded)

Degoulet P. Proc Eur Dial Transplant Assoc. 1980;17:149-54. Diaphane Registry

• 70

70-

• 80

80

Normal LV mass or mild LVH Normal LV mass or mild LVH but no alterations in systolic but no alterations in systolic function. function.

In primary prevention in In primary prevention in apparently healthy persons apparently healthy persons we aim at <140/90, possibly at we aim at <140/90, possibly at normotension by a non normotension by a non-

• pharmacological approach

pharmacological approach

TODAY, about 15% TODAY, about 15%

Young, Young, relatively healthy relatively healthy

BP BP

a composite parameter a composite parameter

ESRD ESRD

• ld Age
• ld Age

~ 40% with past MI ~ 40% with past MI and/or HF and/or HF high proportion of high proportion of pts with pts with ⇑ ⇑ PP PP

Information on components of Information on components of BP and cardiac function BP and cardiac function fundamental in some contexts. fundamental in some contexts. One size may not fit all One size may not fit all

Volume expansion Volume expansion (either occult or (either occult or manifest) manifest)

& Carmine Zoccali

Salt Salt-

• Vol

Vol Salt Salt-

• Vol

Vol Salt Salt-

• Vol

Vol Hypertension in ESRD Hypertension in ESRD

E-pub, ahead of print, 20 Nov 2010

Systolic BP Systolic BP mmHg

mmHg 170 170 160 160 150 150 140 140 130 130 120 120

Baseline 1 Baseline 1-

• year

year

Conventional Frequent

2001;344:102-7

NEJM

Apnea Hypopnea Index Apnea Hypopnea Index 100 100 80 80 60 60 40 40 20 20

Conventional Nocturnal Conventional Nocturnal

Can hypertension in ESRD be controlled by simply intensifying U Can hypertension in ESRD be controlled by simply intensifying UF? F?

150 patients 150 patients randomized randomized

Additional UF, as Additional UF, as tolerated, without tolerated, without changing HD changing HD duration duration

50 patients (standard HD) 50 patients (standard HD) 91 patients 91 patients 43 patients 43 patients Follow up 8 weeks Follow up 8 weeks 100 patients ( 100 patients ( ⇑ ⇑UF) UF)

2009;53:500-507

2009;53:500-507

Systolic BP Systolic BP mmHg

mmHg 150 150 140 140 130 130

diastolic diastolic mmHg

mmHg 85 85 80 80 75 75

0 4 8 weeks 0 4 8 weeks

UF UF

control control

• 7 mmHg

7 mmHg

• 4 mmHg

4 mmHg Very short term Very short term No outcome data (death, CV events) No outcome data (death, CV events) The usefulness of this intervention still unproven The usefulness of this intervention still unproven

• 1.5 kG

Kg

Body Weight

Hypertensives

170 160 150 140 130 85 80 75 70 65 85 80 75 70 65 mmHg mmHg

Baseline 3 months 6 months 64 63 62 61 60 59 58 Baseline 3 months 6 months

Systolic Pressure

Normotensives

Diastolic Pressure

160 150 140 130 120

70 69 68 67 66 65 64

• 9 mmHg
• 4 mmHg

UF INTENSIFICATION IMPROVES HYPERTENSION CONTROL IN HEMODIALYSIS PATIENTS BUT INCREASES ARTERIO-VENOUS FISTULA COMPLICATIONS AND CARDIOVASCULAR EVENTS

Curatola G, Bolignano D, Rastelli S, Caridi G, Tripepi R, Tripepi G, Politi R, Catalano F, Delfino D, Ciccarelli M, Mallamaci F, Zoccali C

Vascular access related hospitalizations ( x 10 patients x 6 months intervals) 3.0- 2.0- 1.0- 0.0- Hospitalizations related with CV complications ( x 10 patients x 6 months intervals) 4.5- 3.0- 1.5- 0.0-

Pre-trial Trial Post-trial

• 18 -13 -12-7 -6-1 0 to 6 +1 +6 +7 +12 months

UF intensification may increase (!) rather than decrease adverse events in dialysis patients. Outcome based trials are needed to test the efficacy of this treatment

Normotensive pts Hypertensive pts

UF INTENSIFICATION IMPROVES HYPERTENSION CONTROL IN HEMODIALYSIS PATIENTS BUT INCREASES ARTERIO-VENOUS FISTULA COMPLICATIONS AND CARDIOVASCULAR EVENTS

Curatola G, Bolignano D, Rastelli S, Caridi G, Tripepi R, Tripepi G, Politi R, Catalano F, Delfino D, Ciccarelli M, Mallamaci F, Zoccali C

Volume expansion Volume expansion (either occult or (either occult or manifest) manifest)

ESRD ESRD

• ld Age
• ld Age

~ 40% with past MI ~ 40% with past MI and/or HF and/or HF high proportion of high proportion of pts with pts with ⇑ ⇑ PP PP

Coronary flow to Coronary flow to myocardium

• ccurs

myocardium

• ccurs

during the diastolic during the diastolic phase of the heart phase of the heart cycle . cycle .

Low diastolic pressure Low diastolic pressure may prompt cardiac may prompt cardiac ischemia in patients ischemia in patients with with ⇑ ⇑ PP PP

⇑ ⇑ PP PP:

: ⇑ ⇑ Systolic Systolic-

• ⇓

⇓ Diastolic or a combination thereof Diastolic or a combination thereof

adjusted for systolic pressure

ESRD ESRD

• ld Age
• ld Age

These observational data suggest that pulse These observational data suggest that pulse pressure should be maintained <60 mmHg pressure should be maintained <60 mmHg by acting directly on arterial rigidity. by acting directly on arterial rigidity.

high proportion of high proportion of pts with pts with ⇑ ⇑ PP PP

adjusted for systolic pressure

Physical exercise, ACE inhibitors, correction of Physical exercise, ACE inhibitors, correction of extracellular volume expansion all reduce arterial extracellular volume expansion all reduce arterial rigidity by direct effects. rigidity by direct effects. No specific trials looking at Pulse Pressure exist No specific trials looking at Pulse Pressure exist in ESRD in ESRD

Volume expansion Volume expansion (either occult or (either occult or manifest) quite manifest) quite common common

ESRD ESRD

• ld Age
• ld Age

~ 40% with past MI ~ 40% with past MI and/or HF and/or HF high proportion of high proportion of pts with pts with ⇑ ⇑ PP PP Does a low BP target increase the risk of death in Does a low BP target increase the risk of death in ESRD patients treated for LVH or systolic ESRD patients treated for LVH or systolic dysfunction and/or overt HF ? dysfunction and/or overt HF ? ..3 trials..

..3 trials..

Zannad F et al., KI 70: 1318-24 2006

ALL CAUSE MORTALITY

(%) 30 35 20 15 1 0 0 12 24 0 12 24 months months

139 139± ±22 22 142 142± ±22 22

397 patients with LVH 397 patients with LVH

50% already on antihypertensive 50% already on antihypertensive treatmeny (no ACE) treatmeny (no ACE)

196 patients 196 patients placebo placebo 201 Fosinopril 201 Fosinopril Fosinopril Fosinopril Risk reduction Risk reduction -

• 7% NS

7% NS

placebo placebo

ESRD ESRD

• ld Age
• ld Age

~ 40% with past MI ~ 40% with past MI and/or HF and/or HF

Cice G . JACC 2003 7;41:1438-44

ALL CAUSE MORTALITY

(%) 50 40 30 20 10 0 12 24 0 12 24 months months

Risk reduction Risk reduction -

• 49%

49%

placebo placebo 123 123± ±7 7 135 135± ±10 10

128 patients 128 patients with LV EF <35% with LV EF <35%

• n ACE inhibitors
• n ACE inhibitors

and other drugs and other drugs

49 patients 49 patients placebo placebo 54 patients 54 patients Carvedilol Carvedilol

Drop Out Drop Out rate: ~10% rate: ~10%

LV systolic dysfunction LV systolic dysfunction

ESRD ESRD

• ld Age
• ld Age

~ 40% with past MI ~ 40% with past MI and/or HF and/or HF

Cice G . JACC 56: 1701-8, 2010

ALL CAUSE MORTALITY

(%) 50 40 30 20 10 0 12 24 36 0 12 24 36 months months

118 118± ±7 7 125 125± ±7 7

Telmisartan Telmisartan P<0.01 P<0.01

placebo placebo

337 patients HF II&III and EF<40% 337 patients HF II&III and EF<40%

• n ACE inhibitors and
• n ACE inhibitors and
• 50% on

50% on Carvedilol Carvedilol

167 patients 167 patients placebo placebo 165 patients 165 patients Telmisartan Telmisartan In the setting of a clinical trial (very In the setting of a clinical trial (very close surveillance) achieved low close surveillance) achieved low pressure in ESRD patients with pressure in ESRD patients with cardiomyopathy treated with ACEi, cardiomyopathy treated with ACEi, Carvedilol and angiotensin II Carvedilol and angiotensin II blockers is associated with a blockers is associated with a marked reduction in the risk of marked reduction in the risk of death. death. The drop

• ut

rate due to The drop

• ut

rate due to hypotension was relatively high in hypotension was relatively high in pts with systolic dysfunction. pts with systolic dysfunction.

Drop Out Drop Out rate: ~10% rate: ~10%

S S &

& C

C

Hypertension in ESRD patients mainly depends on volume Hypertension in ESRD patients mainly depends on volume expansion and high sympathetic activity and these two risk expansion and high sympathetic activity and these two risk factors are at least in part patho factors are at least in part patho-

• physiologically intertwined.

physiologically intertwined. High pulse pressure is a strong risk factor in dialysis patien High pulse pressure is a strong risk factor in dialysis patients. ts. Available data suggest that direct interventions aimed at Available data suggest that direct interventions aimed at modifying arterial rigidity (rather than BP per se) are needed. modifying arterial rigidity (rather than BP per se) are needed. Frequent dialysis substantially reduces BP in ESRD and Frequent dialysis substantially reduces BP in ESRD and ameliorates LVH. Strategies based on UF intensification may ameliorates LVH. Strategies based on UF intensification may increase adverse events. increase adverse events. Achieved low pressure in ESRD patients with Achieved low pressure in ESRD patients with cardiomyopathy treated with Carvedilol and angiotensin cardiomyopathy treated with Carvedilol and angiotensin blockers is associated with a marked reduction in the risk blockers is associated with a marked reduction in the risk of

• f
• death. Close clinical surveillance is fundamental in these
• death. Close clinical surveillance is fundamental in these

patients. patients.