Transcript 1. dia

HYPERTENSION IN PATIENTS
ON HEMODIALYSIS
Csaba Farsang
1st Department of Medicine
Semmelweis University Medical Faculty
Budapest, Hungary
ESH
Brescia
Summer 16th Sept.
School
2004
Hypertension and the Kidney
Macroproteinuria
Nephrotic
proteinuria
Microalbuminuria
Endothelial
dysfunction
Risk factors
Diabetes mell.
Hypertentension
ESRD
Death
Progression of chr. kidney disease (CKD)
Degree of renal insufficiency
RENAL INSUFFICIENCY
GFR ml / min
Mild
60-89
Moderate
30-59
Severe
15-29
End stage kidney failure
< 15
[ 140-age (yrs) ] x body weight (kg)
GFR calc. =
48.8 x serum creatinine (umol/l)
Segura J, Ruilope LM, Zanchetti A. J.Hypertens.2004;22:1635-1639.
x 60 x
M (male) = 1,
F (female) = 0,85
Pathophysiological changes in chronic kidney
failure
Elektrolyte and water
metabolism
Protein, carbohydrate, lipid and
energy metabolism
Impairment of biological
functions
Immune system,
inflammation, oxidative
stress
Hormonal
changes
Blood cell
production
Cardiovascular system
Gastrointestinal system
CNS
Skin
Water Metabolism in Kidney Failure
Disturbed
sodium and
water
metabolism
Nephron-medullary loss
ADH effect decreases
Single-nephron GFR
Isosthenuria
Chronic
Kidney Failure
Dehydrationhypernatraemia
Water „intoxication”hyponatraemia
Short and long-term CV consequences of salt retention
Cardiac Output
Extracellular volume
Blood volume
Vasopressor (RAAS, NA, VA, ET) activity increases
Vasodilator „tone” decreases (renomedullary lipids, kinins, vasodilator prostaglandins)
Activity of endogenous inhibitors of NO synthesis increases (asymmetric dimethyl-arginin)
(Mean Arterial Pressure)
Severe renal
impairment
Moderate renal
impairment
ExtraCellular Volume)
Effects of extracorporal therapies
hemodialysis (HD) or ultrafiltration (UF)
Changes in blood volume and interstitial fluid volume of a patient, who entered the
hospital in overfilled state and was ultrafiltered (UF) daily
Prior to UF
Immediately after UF
Day 24
Day 1
Koomans HA. Body fluid dynamics during dialysis In:Zoccali (ed). Clinical hypertension in Nephrology. Contr.Nephrol. 1996;119:173-181
Extracellular volume (ECV) and blood volume (BV)
in chronic renal failure
BV cannot be increased indefinitely
Koomans HA et al. Kidney Int. 1986; 30:730-735
MAP and ECFV
The determinant of BP is the blood volume
Koomans HA et al. Kidney Int. 1986; 30:730-735
Predialytic Extracellular Volume (ECV) and
Mean Arterial Pressure (MAP) during the course of HD
MAP
ECV
Charra B. et al. Am.J.Kidney Dis. 1998;32:720-724
Effects of ultrafiltration on MAP, HR, PV, and COP
(Colloid Osmotic
Pressure)
Koomans HA et al. Kidney Int. 1986; 30:730-735
HEMODYNAMIC CHANGES DURING
EXTRACORPOREAL THERAPIES
in normotensive pts
HEMODYNAMIC
PARAMETERS
ARTERIAL PRESSURE
CARDIAC OUTPUT
STROKE VOLUME
HEART RATE
SYSTEMIC
RESISTANCE
UF
HD
HF
Hypertension is common in dialysed patients
- at pre-dialysis state >80%,
- in patients with hemodialysis >60%,
- in those with peritoneal dialysis >30 %
The leading cause of death in dialysed patients
is cardiovascular!
Rahman M, Smith MC. Hypertension in hemodialysis patients. Current Hypertension Reports 2001; 3: 496-502.
Increased cardiovascular mortality in
end stage renal failure
100
ESRD
cardiovascular
mortality/year (%)
10
1
0,1
unselected population
0,01
25-34
35-44
45-54
55-64
65-74
75-84
> 84
Age group (year)
Sarnak & Levey 2000
Impact of BP on Survival in Hemodialysis Patients
depending on the presence of IHD
SBP <160 mm Hg
SBP >160 mm Hg
SBP >160 mm Hg
SBP <160 mm Hg
Kimura G. et al. Am.J.Hypertens.1996;9:1006-1012
But:
in dialysed patients the relationship between
hypertension and cardiovascular mortality/morbidity
is controversial because of
- the high prevalence of co-morbid conditions,
- by the underlying vascular pathology and
- by the effects of
- dialysis on blood pressure
- age
- left ventricular hypertrophy/dysfunction (also
more prevalent in patients with hypertension)
- poor nutrition .
DM
Life expectancy of hemodialysed diabetics
(prospective study in Germany)
Koch, NDT (1997) 12: 2603
In patients on hemodialysis, hypertension has been
associated with:
- stroke,
- MI,
- CHF,
- ventricular arrhythmias and
- progression of atherosclerosis
Increased rate of vascular calcification in ESRD
Normal renal function
ESRD
JACC, 2002
Characteristics of cardiovascular
complications in patients with dialysis
Hypertension present in 60-90%
LVH: 90%
Total mortality: 12-25% - CV mortality: 60-70%
CHD: 17x mortality
Risk factors
1 mm Hg icrease in MAP = 35% increase in CV morbidity
5 mm Hg increase in MAP = 3% increase in the risk of LVH
„J” or „U” shaped curve exists for BP and morbidity
Systolic blood pressure and cardiovascular mortality
in dialysed patients
7
6
5
4
3
2
1
0
80
90
10
0
11
0
12
0
13
0
14
0
15
0
16
0
17
0
18
0
19
0
20
0
R
I
S
K
Systolic BP ( mm Hg)
Zager PG, et al.: "U" curve association of blood pressure and mortality in hemodialysis patients.
Kidney Int 1998; 54: 561-569.
Causes of increased cardiovascular
mortality in pts with ESRD
Possible CV risk factors in ESRD:
- Hypertension,
Higher A-II level, sympathetic activity,
- Dyslipidemia
Micro-inflammatory state (CRP<)
- Anemia
LVH
- Hypervolemia
Salt overload
- Hyperhomocysteinemia
Malnutrition
- NO-deficiency
Increased oxidative stress
- Uremic toxins
- Sec. hyperparathyroidism
Hyperphosphatemia
- Atherosclerosis
Reduced vascular compliance
- Fetuin-A level decreases
Relative risk of cardiovascular mortality
associated with various cholesterol levels in
dialysis patients
Cholesterol
(mg/dL)
All
patients
Patients with
inflammation or
malnutrition
Patients without
inflammation or
malnutrition
<160
1.00
1.00
1.00
160-199
0.80
0.85
1.67
200-239
1.16
0.97
3.14
>240
0.87
0.72
4.60
?
Liu Y et al. JAMA 2004; 291:451-459.
Causes of increased cardiovascular
mortality in pts with ESRD
Possible CV risk factors in ESRD:
- Hypertension,
Higher A-II level, sympathetic activity,
- Dyslipidemia
Micro-inflammatory state (CRP<)
- Anemia
LVH
- Hypervolemia
Salt overload
- Hyperhomocysteinemia
Malnutrition
- NO-deficiency
Increased oxidative stress
- Uremic toxins
- Sec. hyperparathyroidism
Hyperphosphatemia
- Atherosclerosis
Reduced vascular compliance
- Fetuin-A level decreases
Anemia Is a Mortality Multiplier
DM/CHF Have The Same Mortality Risk As
Chr. Kidney Disease/Anemia
7.3
8.0
7.0
6.0
6.3
6.0
4.6 4.7
5.0
4.0
3.6 3.7 3.7
4.0
3.0
2.0
2.0 2.0
1.0
2.4 2.4
2.9
1.5
1.0
0.0
Collins, AJ. Adv Stud in Med. 2003;3(3C):S14-S17.
Causes of increased cardiovascular
mortality in pts with ESRD
Possible CV risk factors in ESRD:
- Hypertension,
Higher A-II level, sympathetic activity,
- Dyslipidemia
Micro-inflammatory state (CRP<)
- Anemia
LVH
- Hypervolemia
Salt overload
- Hyperhomocysteinemia
Malnutrition
- NO-deficiency
Increased oxidative stress
- Uremic toxins
Obesity
- Sec. hyperparathyroidism
Hyperphosphatemia
- Atherosclerosis
Reduced vascular compliance
- Fetuin-A level
decreases
Characteristics of fetuin-A
(a2-Heremans Schmid glycoprotein, AHSG)
Molecular weight:
62 kD
Serum Conc.: 0.5-1.0 g/l
Origin:
Liver (Hepatocytes)
Function:
- Negative acute-phase reactant inhibits
insulin receptor autophosphorylation,
- TGF-b Antagonist
Inhibitor of Ca X PO4 precipitation,
50% of precipitation inhibitory effect of serum
KO mice:
Metastatic soft tissue,
cardiovascular (intra-arterial) calcification
Clinic:
Decreased se. conc. in ESRD
Serum fetuin-A (AHSG) levels as a prognostic marker of
all-cause and cardiovascular mortality in ESRD
Cardiovascular mortality
Proportion surviving (%)
Proportion surviving (%)
All-cause mortality
Follow-up (months)
Follow-up (months)
Ketteler et al., Lancet, 2003
Causes of increased cardiovascular
mortality in pts with ESRD
Possible CV risk factors in ESRD:
- Hypertension,
Higher A-II level, sympathetic activity,
- Dyslipidemia
Micro-inflammatory state (CRP<)
- Anemia
LVH
- Hypervolemia
Salt overload
- Hyperhomocysteinemia
Malnutrition
- NO-deficiency
Increased oxidative stress
- Uremic toxins
Obesity
- Sec. hyperparathyroidism
Hyperphosphatemia
- Atherosclerosis
Reduced vascular compliance
- Fetuin-A level decreases
Obesity and ESRD
Survival of the chronically dialysed obese patients is
longer than that of non-obese ones (But! mostly in AfroAmericans)
Obese patients are frequently under-dialysed (!?)
After renal transplantation the survival of grafts are
shorter in obese than in non-obes patients.
Etiology of hypertension in dialysed patients
I
- sodium and volume excess due to diminished sodium
excretory capacity of kidney
- activation of the renin-angiotensin-aldosterone system
- increased activity of the sympathetic nervous system
- increased endogenous vasoconstrictor (endothelin-1,
Na-K-ATPase inhibitors, adrenomedullin), and
- decreased vasodilator (nitric oxide, prostaglandins)
compounds
Henrich WL, Mailloux LU. Hypertension in dialysis patients. Rose B. UpToDate online 11.3, 2004, http://www.uptodate.com
Etiology of hypertension in dialysed patients
II
- frequent administration of erythropoietin
- increased intracellular calcium content, induced by
parathyroid hormone excess
- increased arterial stiffness, caused by calcification of
arterial tree,
- pre-existent hypertension
- nocturnal hypoxemia because of frequent sleep apnea
Henrich WL, Mailloux LU. Hypertension in dialysis patients. Rose B. UpToDate online 11.3, 2004, http://www.uptodate.com
Blood pressure measurement
in dialysis patients
I
Pre- or post-dialysis blood pressure measurements
in patients with hemodialysis may be misleading for
the diagnosis of hypertension:
- the pre-dialysis systolic blood pressure may
overestimate while
- the post-dialysis systolic blood pressure may
underestimate
the mean inter-dialytic SBP by 10 mmHg;
DBP by 7 mmHg
Luik AJ, Kooman JP, Leunissen ML. Hypertension in hemodialysis patients: Is it only hypervolaemia?
Nephrol Dial Transplant 1997; 12: 1557-60.
Blood pressure measurement
in dialysis patients
II
Ambulatory blood pressure monitoring (ABPM)
appears to be reproducible in pts. on hemodialysis.
Blood pressure is frequently
- high in pre-dialysis state,
- it falls immediately after dialysis, and then
- it gradually increases during the inter-dialytic period.
ABPM may be useful in determining “systolic blood pressure
load” which is an important factor in the development of
left ventricular hypertrophy.
- Pre-dialysis blood pressure correlates better with
LVH than post-dialysis blood pressure.
- The dialyzed patients usually lose the diurnal variation
in blood pressure and consequently these patients develop
nocturnal hypertension.
- Home blood pressure measurement, an increasingly popular
method, may be useful to estimate the blood pressure control
also in dialysed patients
Conion PJ, Walshe JJ, Heinle SK et al. Predialysis systolic blood pressure correlates strongly with mean 24-hour systolic blood pressure
and left ventricular mass in stable hemodialysis patients. J Am Soc Nephrol 1996; 7: 2658-63.
Agarwal R. Role of home blood pressure monitoring in hemodialysis patients. Am J Kidney Dis 1999; 33: 682-7.
Hypertension Severity Index (HSI)
HSI score
0
1
2
3
Systolic BP (mmHg)
Diastolic BP (mmHg)
< 150
150-159
160-179
> 179
< 90
90-99
100-109
> 109
To calculate for an individual dialysis treatment sum the
- pre-dialysis systolic and diastolic, and
- post-dialysis systolic and diastolic blood pressure scores.
The HSI can range from 0 to 12.
Management of high blood pressure in
hemodialysis patients
Improved survival due to adequate blood pressure
control of dialysed patients has been clearly demonstrated,
stressing the importance of adequate antihypertensive treatment.
Salem MM, Bower J. Hypertension int he hemodialysis population: any relation to one-year survival? Am J Kidney Dis 1996; 28: 737-40.
Target blood pressure in dialysed hypertensive patients
Causal measurement, mercury
sphygmomanometer
Dialysed elderly patient
<150/90 mm Hg
Dialysed young patient or
Dialysed patient with T2DM
<120/80 mm Hg
Hypertensive nephropathy
120-130/75-80 mm Hg
Proteinuria (>1 g/day)
<125/75 mm Hg
Renovascular hypertension
<130/85 mm Hg
ABPM daytime average: < 135/85 mm Hg, nighttime average: < 120/80 mm Hg.
Henrich WL, Mailloux LU. Hypertension in dialysis patients. Rose B. UpToDate online 11.3, 2004, http://www.uptodate.com
Target blood pressure of hypertensive
dialysed patients
For most patients on dialysis (mainly in older age):
the goal blood pressure is less than an average value
below 150/90 mmHg, on no medication.
The reasonable target goal of a mean ABPM value
- during the day < 135/85 mmHg
- by night < 120/80 mmHg.
CAUTION! Very low systolic blood pressure (<110 mm Hg)
may be associated with enhanced cardiovascular mortality
(“J” or “U” shaped curve )
Henrich WL, Mailloux LU. Hypertension in dialysis patients. Rose B. UpToDate online 11.3, 2004, http://www.uptodate.com
Algorithm for blood pressure control
in dialysis patients
I
1. Estimate dry weight
2. Determine Hypertension Severity Index (HSI)
3. Initiate non-pharmacological treatment
4. Attain dry weight
5. Start or increase the dose of antihypertensives
to maintain BP below 150/90 mmHg
Fishbane S, Maseka JK, Goreja MA et al. Hypertension in Dialysis Patients . In Cardiovascular Disease in End-stage Renal Failure.
Loscalzo J, London GM. Oxford University Press, New York, USA, 2000. pp 471-484.
Clinical definitions of stable “dry weight”
- either the blood pressure has normalized or
- symptoms of hypervolemia disappear (not merely the absence
of edema);
- after dialysis seated blood pressure is optimal, and
- symptomatic orthostatic hypotension and clinical signs of
fluid overload are not present;
- at the end of dialysis patients remain normotensive until the
next dialysis without antihypertensive medication.
Algorithm for blood pressure control
in dialysis patients
II
6. If BP is not controlled or dry weight not attained in 30 days,
consider:
- 24-48 hours ABPM
- increasing the duration of dialysis to facilitate removal
of fluid and attainment of dry weight
- increasing the dose or number of antihypertensives
7. If BP remains uncontrolled, consider:
- evaluating for secondary forms of hypertension
- peritoneal dialysis
- bilateral nephrectomy (exceptional)
Fishbane S, Maseka JK, Goreja MA et al. Hypertension in Dialysis Patients . In Cardiovascular Disease in End-stage Renal Failure.
Loscalzo J, London GM. Oxford University Press, New York, USA, 2000. pp 471-484.
Non-pharmacological treatment of
hypertension in dialysed patients
Important remarks:
-Control of plasma volume can either normalize or help
normalize blood pressure in dialysed patients.
- Fluid removal predisposes to episodes of hypotension during
hemodialysis treatment.
-Hypotension is one of the important cardiovascular
risk factors.
Non-pharmacological treatment of
hypertension in dialysed patients
- Aerobic exercise
- Control of salt and fluid intake
- Cessation of smoking
- Weight reduction
- Avoidance of alcohol
- Long, slow and more frequent hemodialysis treatment
- Bilateral nephrectomy
Non-pharmacological treatment of
hypertension in dialysed patients
- Aerobic exercise
- Control of salt and fluid intake
- Cessation of smoking
- Weight reduction
- Avoidance of alcohol
- Long, slow and more frequent hemodialysis treatment
- Bilateral nephrectomy
To avoid large inter-dialytic weight gains, patients should
restrict salt intake (750 to 1000 mg of sodium/day). This also
decreases thirst and improves patient’s compliance.
A fixed or a programmed decrease in the concentration of
sodium in the dialysate (from 155 to 135 mEq/L) with
combination of dietary salt restriction, may result in smaller
doses of antihypertensive drugs to control blood pressure.
Non-pharmacological treatment of
hypertension in dialysed patients
- Aerobic exercise
- Control of salt and fluid intake
- Cessation of smoking
- Weight reduction
- Avoidance of alcohol
- Long, slow and more frequent
treatment
- Bilateral nephrectomy
hemodialysis
The long, slow hemodialysis treatment (eight hours, and
three times a week) is associated with the maintenance of
normotension without medications in almost all patients,
as this decreases afferent renal nerve activity and efferent
sympathetic activation.
Nocturnal hemodialysis treatment (six or seven nights a
week during sleep hours) can also normalize blood pressure
without medications in most of the patients.
More frequent hemodialysis treatment (two hours six times
per week) may also be associated with normotension without
medications and with regression of left ventricular hypertrophy.
Non-pharmacological treatment of
hypertension in dialysed patients
- Aerobic exercise
- Control of salt and fluid intake
- Cessation of smoking
- Weight reduction
- Avoidance of alcohol
- Long, slow and more frequent hemodialysis treatment
- Bilateral nephrectomy
Bilateral nephrectomy may be considered in:
- noncompliant individuals
- with life-threatening hypertension
- blood pressure cannot be controlled with any of the
above detailed dialysis modality.
Pharmacological treatment of hypertension
in dialyzed patients
Suggested use of antihypertensive drugs in hemodialysis patients
(which drug - when)
Drugs
ACE inhibitors
Compelling indication
LVH, CHF, DM,
DHP-CCB
Non-DHP-CCB
CHD
CHD
BBL
CHD
Specific side-effects
Special precautions
Anaphylactoid reactions with
AN69 dialyzer
No comb. with BBL
Excessive bradycardia
with liposoluble compounds
Post-dialysis rebound
with methyldopa
No comb with
non-DHP-CCB
Centrally act.
agents
none
Avoid
ABL
Dyslipidemia
Insulin resistance
Severe hypotension
Direct
vasodilators
Hypertensive
crisis
In hospital use
Use of antihypertensive drugs in patients
with chr. parenchymal renal disease
Thiazide diuretics
ACE-inhibitors
ARB
Calcium antagonists
Beta-blockers
Centrally acting drugs, direct vasodilators
Progression
of
kidney
disease
Some remarks for antihypertensive drug classes
ACE-inhibitors:
-effective and well tolerated
- reduce mortality also of dialysed patients (age < 65 yrs) independently
from the antihypertensive effect
- can reduce the synthesis/secretion of erythropoietin (anemia !)
- can trigger an anaphylactoid reaction in patients dialyzed with
AN69 dialyzer
Clinical Endpoint Data for ESRD in Type 2
Diabetes with ACE Inhibitors
Endpoints Studied
ACE Inhibitor Trials
in Type 2 Diabetics
with >1 Yr Follow-up
Total
Reduction of
Sample Proteinuria
Ravid et al Ann Int Med 1993
94
Lebovitz et al Kid Int 1994
121
Bakris et al Kid Int 1996
52
Ahmad et al Diab Care 1996 103
Nielsen et al Diabetes 1997
43
UKPDS et al Br Med J 1998
758
Fogari et al J Hum Hypertens 1999 107
ABCD Diab Care 2000
470
Ruggenenti et al (REIN)
352 (27)**
Am J Kid Dis 2000
MICRO-HOPE** Lancet 2000 3577
Reduction of
Fall in GFR
Reduction in Risk
of ESRD*
YES
YES
YES
YES
YES
YES
YES
YES
NO
YES
YES
YES
YES
YES
YES
YES
YES
YES
NO
NO
NO
NO
NO
NO
NO
NO
YES**
YES
NO
YES***
* Reduction in the risk of end-stage renal disease (renal transplant or dialysis)
** Only 27 (8%) of the 352 patients in this study were Type 2 diabetics
*** In this study there was no reduction of risk for renal dialysis
for ramipril compared to placebo (p = 0.70)
Main outcomes in patients with renal
insufficiency (serum creatinine  1.4
mg/dl)
60
Prim.
outcome 55 64
40
36 40 32
Events (per 1000 pt-yrs)
80
46
20
0
40
< 1.4
 1.4
CV Death
37
28
30
20
16 18 14
20
10
0
< 1.4
 1.4
All
Placebo
Ramipril
MI
60
50
40
30
20
10
0
48
40
25 28 22
< 1.4
60
50
40
30
20
10
0
All Death
25 27 24
< 1.4
34
1.4
57
43
32
 1.4
Some remarks for antihypertensive drug classes
ARB:
- limited experience
- losartan does not enhance the risk of anaphylactoid dialyzer-reactions
- no dose adjustment is necessary in renal failure in the absence of
volume depletion.
Some remarks for antihypertensive drug classes
CCB:
- effective and well tolerated
- do not require supplementary post dialysis dosing
-26 % (significant) reduction in cardiovascular mortality
in USRDS Study
BBL:
- side effects include CNS depression (mainly lipid-soluble drugs),
bradycardia, and heart failure
- preferable beta-blocker may be atenolol, labetalol, carvedilol
Some remarks for antihypertensive drug classes
ABL:
- help counteract the increase in sympathetic nerve activity.
- on long-term treatment the favourable metabolic effects
on lipids and insulin resistance might be advantageous.
- preferred mostly in antihypertensive combinations.
Centrally acting drugs:
- methyldopa, clonidine, guanfacine have more side effects,
- moxonidine, rilmenidine (imidazoline I1 receptor agonists are safe
and effective, but only limited experience is available.
Special situations
I
Refractory hypertension
- minoxidil – the strongest direct vasodilator - may be effective
- patients may benefit from switching to continuous ambulatory
peritoneal dialysis (CAPD
Erythropoietin (EP)-induced hypertension
- decrease the actual dry weight
- decrease the dose (if possible)of EP or interrupt treatment
- reintroduce treatment later at lower dose
- introduce or increase antihypertensive medication with preference
of CCB
Ribstein J, Mourad G, Argiles A et al. Hypertension in end-stage renal failure. In Complications of Dialysis.
Ed. by Lameire N, Mehta RL. Marcel Dekker, Inc. New York, USA, 2000. pp 274-287.
Special situations
II
Diabetic dialysis patients
Characteristics
- the number of T2DM is rapidly increasing
- patients are generally hypertensive
- exchangeable sodium is increased
- frequent:
- orthostatic hypotension due to autonomic neuropathy with
severe symptoms
- coronary artery disease
- peripheral atherosclerosis
Special situations
II
Diabetic dialysis patients cont.
Treatment
To avoid the risk of severe hypotension:
- longer dialysis
- slow ultrafiltration rate
- hemofiltration
- glucose-containing dialysate can be used.
- ACE inhibitors and/or ARBs may prevent end-organ vascular
diseases
- CCBs are very effectively reduce blood pressure but may result in
severe hypotensive episodes
- BBL-benefit is particularly significant in patients with CHD
Doubling of Serum Creatinine
Risk Reduction: 25%
p=0.006
L
24
36
48
Months
P (+ CT) 762
L (+ CT) 751
689
692
554
583
10
12
50
0
12
L
P (+ CT) 762
L (+ CT) 751
10
0
20
0
P
20
Risk Reduction: 28%
p=0.002
P
0
295
329
36
52
% with event
% with event
30
ESRD
30
% with event
RENAAL
Primary Components
715
714
24
Months
610
625
36
347
375
48
42
69
ESRD or Death
40
Risk Reduction: 20%
p=0.010
30
P
L
20
10
0
0
P (+ CT) 762
L (+ CT) 751
Brenner BM et al New Engl J Med 2001;345(12):861-869.
12
715
714
24
36
Months
610
347
625
375
48
42
69
RENAAL
First Hospitalization for Heart Failure
% with event
20
Risk Reduction: 32%
p=0.005
P
15
10
L
5
0
P (+CT)
L (+CT)
0
12
762
751
685
701
Brenner BM et al New Engl J Med 2001;345(12):861-869.
24
Months
616
637
36
48
375
388
53
74
Special features of frequently used
antihypertensive drugs in hemodialysis patients
Diuretics
-avoid thiazide-type drugs, K-sparing drugs (amiloride, spironolactone)
acetazolamide
- furosemide is useful but it has ototoxicity anbd augment
aminoglycoside-toxicity
BBL
- no change in the dose of carvedilol, labetalol, metoprolol, pindolol,
propranolol (active metabolites!), tertatolol, timolol
ACEi
- fosinopril has dual excretion (51%:kidney, 50% liver), therefore no
need to reduce the dose
Special features of frequently used
antihypertensive drugs in hemodialysis patients
ARBs
- no need to change the dose of irbesartan, losartan, olmesartan,
telmisartan and valsartan
CCB
- DHP-CCB: no need to change the dose
- verapamil: the dose should be reduced by 50 % (active metabolites!)
Direct vasodilators
- no need to change the dose of diazoxide, hydralazine, minoxidil
- nitroprusside-Na: thiocyanate is dialysable
Antihypertensive drugs in dialysis patients
Summary (when – which drug)
Cliniucal situation
CHF
Post-MI
LVH diast.dysf.
COPD
CHD
Drugs of choice
ACEi, ARB, BBL
ACEi, BBL
BBL, dilti., verap.
ACEi, ARB, CCB
BBL, ACEi, CCB
ARB
Not recommended
Dir. vasodil.
Dir. vasodil., α1BL
BBL
Locatelli F. et al. Nephrol. Dial. Transoléant. 2004; 19:1058-1068
Conclusions
-The progress of dialysis technology leads to better tolerated dialysis
treatment and more adequate removal of sodium-water overload.
-Treatment of hypertension in dialysis patients still remains a careful
clinical judgment for:
- adequate evaluation of the dry weight
- choice of adequate treatment time and frequency.
-In those patients in whom ultra-filtration and maintenance of dry
weight do not adequately control hypertension,
antihypertensive medications are indicated
Butt G, Winchester JF, Wilcox CS. Management of hypertension in patients receiving dialysis therapy. In Therapy of Nephrology and
Hypertension. A companion to Brenner and Rector’s The Kidney ed. by HR Brady, CS Wilcox., W.B. Saunders Company, Philadelphia, USA, 1999.
Jacobs C. Medical management of the dialysis patients. In Oxford Textbook of Clinical Nephrology. Vol.3. Ed. By Davison AM, Cameron JS,
Grünfeld J-P, Kerr DNS, Ritz E, Winearls G., Oxford Medical Publications, 1998. pp 2089-111.
Renal Parenchymal Hypertension. Blood pressure in Chronic Dialysis Patients. In NM Kaplan: Kaplan’s Clinical Hypertension, Lipincott
Williams & Wilkins, Philadelphia, USA, 2002.
London G, Marchais S, Guerin AP. Blood pressure control in chronic hemodialysis patients. In Jacobs C, Kjellstrand CM, Koch KM,
Winchester JF: Replacement of renal function by dialysis, Kluwer Academic Publishers, Dordrecht, Netherlands, 1996. pp 966-989.
Misra M, Reams GP, Bauer JH. Hypertension in Patients on Renal Replacement Therapy. In Hypertension: A companion to Brenner and Rector’s
The Kidney ed. by S Oparil, MA Weber, W.B. Saunders Company, Philadelphia, USA, 2000.
Passlick-Deetjen J, Ritz E. Management of the Renal Patient: Expert’s Recommendations and Clinical Algorithms on Cardiovascular Risk Factors.
Good Nephrological Practice. ERA-EDTA. Pabst Science Publishers, 2001.
Locatelli F, Covic A, Chazot C, Leunissen K, Luno J, Yaqoob M. Hypertension and cardiovascular risk assessment in dialysis patients. Nephrol
Dial Transplant 2004; 1-11, DOI: 10.1093/ndt/gfh103
How well are we doing?
Guidelines And Practice (GAP) Study
Association of patient characteristics with uncontrolled systolic BP
Decreases   Increases
200 family physicians
17,000 patients
1.43 (1.32-1.56)
1.57 (1.43-1.72 )
1.41 (1.30-1.53 )
1.19 (1.08-1.32)
1.20 (1.06-1.36)
1.26 (1.15-1.39)
1.31 (1.11-1.54)
3.78 (3.19-4.48)
1.01 (0.86-1.19)
Guidelines And Practice (GAP) Study
Association of patient characteristics with uncontrolled diastolic BP
Decreases   Increases
1.06 (0.97-1.17)
1.91 (1.73-2.10)
1.47 (1.35-1.61)
1.46 (1.31-1.63)
1.22 (1.07-1.40)
1.42 (1.28-1.57)
1.38 (1.17-1.63)
4.27 (3.70-4.92)
1.13 (0.95-1.33)
Guidelines And Practice (GAP) Study
Association of patient characteristics with the physician being “less
stringent” than guidelines compared to the physician being “more
stringent” than guidelines
decreases
increases
16x

We should do much better…..
THANKS
FOR YOUR ATTENTION
Next ESH Summer School:
September 24 – 30, 2005
In: Visegrád, Hungary
THANK YOU FOR YOUR ATTENION
Additional slides:
Brescia, University Campus
Thank you for your attention
Role of Hypertension in
the Pathogenesis of ESRD
% 30
international
Hungarian
25
20
15
10
5
0
1980
1990
1997
2000
Multivariate predictors of kidney
disease
Risk factor
Odds
ratio
95% CI
Age (per 10-year increment)
2.36
2.0-2.78
Diabetes (yes vs no)
2.6
1.44-4.70
Smoking (yes vs no)
1.42
1.06-1.91
GFR <90 mL/min per 1.73 m2
3.01
1.98-4.58
BMI (per standard deviation unit)
1.23
1.08-1.41
Hypertension (yes vs no)
1.57*
1.16-2.12
HDL cholesterol (per standard
deviation unit)
0.82*
0.71-0.94
*Individual predictors of kidney disease; not entered into multivariate analysis
Fox CS et al. JAMA 2004; 291:844-50.
Hypertension and Kidney Failure
A Vitious Circle I.
The tone of the aferent arterioles does not increase adequately,
the systemic blood pressure increases glomerular
pressure.
 Higher glomerular pressure and consequently the higher
flow streches the glomerular cells.
 Ultrafiltration of proteins increases.
 Because of progressive glomerular sclerosis the number of
glomeruli decreases
impairment of kidney function
Hypertension and Kidney Failure
A Vitious Circle II.
 Na+ excretion >
extracellular fluid volume <

Cardiac output <

Vasopressor (RAAS, NA, VA, ET) activity increases

Vasodilator „tone”
vasodilator prostaglandins)

Activity of endogenous inhibitors of NO synthesis increases
(asymmetric dimethyl-arginin)
decreases
(renomedullary
lipidek,
kinins,
Etiology of hypertension in chr. parenchymal
renal disease
• Hypernatraemia, hypervolaemia
• RAAS activation
• Ratio of vasoconstrictor / vasodilator substances
changes (endothelin-1< / NO>)
• PTH level <
• Number of nephrons >
• Progression of hypertensive disease
• Erythropoietin therapy
Pathogenesis of renoparenchymal
hypertension
decrease in renal function / parenchyma
GFR decreases
Na+ and water retention
increase in blood volume
pressor sensitivity increases
TPR increases
CO increases
hypertension
THE EFFECT OF HEMODIALYSIS
ON LV FUNCTION
SV
ESV EDV EF
VCF S-F
REG
YES
UF
YES
IVHD
NO
Risk factors in dialysed patients
Age: 1,04
Cardiovascular illness: 1,59
Hypertension: 0,55
Anemia: 0,9-1,55
Dislipidemia
Diabetes mellitus: 1,99
+
Malnutrition (serum albumin)
Body weight
Quality of dialysis therapy
Duration of dialysis
Relative risk of all-cause mortality associated
with various cholesterol levels in dialysis patients
Cholesterol
(mg/dL)
All
patients
Patients with
inflammation or
malnutrition
Patients without
inflammation or
malnutrition
<160
1.00
1.00
1.00
160-199
0.74
0.76
1.23
200-239
0.74
0.71
2.33
>240
0.71
0.62
3.22
Liu Y et al. JAMA 2004; 291:451-459.
Jafar TH et al: Progression of chronic kidney disease: The role of blood
pressure control, proteinuria, and angiotensin-convering enzyme inhibition
Ann Intern Med 2003; 139: 244-253
A CV Continuum: the Beginning and the End:
Health Status/QOL
Lower
Higher
From High Blood Pressure to
Renal and Cardiac Damage
Normotensive H y p e r t e n s i o n
Decline in
Glomerular
Filtration
Rate
Vascular
Hypertrophy
Left Ventricular
Dysfunction
Renal Impairment
Stroke
Heart
Failure
Kidney Failure
HD
Death
Time, years
Dzau V, Braunwald E. Am Heart J. 1991;121:1244–1263.
Role of Proteinuria
Percentage of patients having a cardiovascular
event (and hazard ratio) per decile of UA / CR
(mg/mmol)
Decile of
UA / CR
<0.25
0.250.41
0.410.59
0.590.82
0.821.16
Composite
CV end
point* (% of
patients)
5.6
7.2
7.7
7.9
8.8
Hazard ratio
1.0
1.2
1.4
1.3
1.4
Wachtell K et al. Ann Intern Med 2003;139:901-6.
Features of antihypertensive therapy
in dialysed patients
ARB
CCB
Decrease risk
factors
and /or
ACE-i
Organprotection
BBL
Decrease the
activity of
Centrally acting drugs
sympathetic
nervous system
vasodilator
Clinical definitions of stable “dry weight”
- either the blood pressure has normalized or
- symptoms of hypervolemia disappear (not merely the absence
of edema);
- after dialysis seated blood pressure is optimal, and
- symptomatic orthostatic hypotension and clinical signs of
fluid overload are not present;
- at the end of dialysis patients remain normotensive until the
next dialysis without antihypertensive medication.
Effects of proteinuria on stroke and on CHD in
T2DM
A: U-Prot <150 mg/L
B: U-Prot 150–300 mg/L
C: U-Prot >300 mg/L
40
1.0
P <0.001
0.9
A
Survival 0.8
30
B
Incidence
(%) 20
C
10
0.7
0.6
0.5
Overall: P <0.001
0
0
0 10 20 30 40 50 60 70 80 90
Months
Stroke
CHD
Events
U-Prot = urinary protein concentration.
Miettinen H et al. Stroke. 1996;27:2033–2039.