1. dia

1
HYPERTENSION IN PATIENTS ON HEMODIALYSIS
Csaba Farsang 1st Department of
Medicine Semmelweis University Medical
Faculty Budapest, Hungary
Brescia 16th Sept. 2004
ESH Summer School
2
Progression of chr. kidney disease (CKD)
Hypertension and the Kidney
Macro- proteinuria
Nephrotic proteinuria
Micro- albuminuria
ESRD
Endothelial dysfunction
Risk factors Diabetes mell. Hypertentension
Death
3
Degree of renal insufficiency
RENAL INSUFFICIENCY GFR ml / min Mild
60-89 Moderate 30-59
Severe 15-29 End
stage kidney failure lt 15
140-age (yrs) x body weight (kg) 48.8 x serum
creatinine (umol/l)
GFR calc.
x 60 x
M (male) 1, F (female) 0,85
Segura J, Ruilope LM, Zanchetti A.
J.Hypertens.2004221635-1639.
4
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
Blood cell production
Hormonal changes
Cardiovascular system
Gastrointestinal system
CNS
Skin
5
Water Metabolism in Kidney Failure
Disturbed sodium and water metabolism
Nephron-medullary loss
ADH effect decreases
Single-nephron GFR
Isosthenuria
Chronic Kidney Failure
Dehydration-hypernatraemia
Water intoxication-hyponatraemia
6
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)
7
Severe renal impairment
(Mean Arterial Pressure)
Moderate renal impairment
ExtraCellular Volume)
8
Effects of extracorporal therapies hemodialysis
(HD) or ultrafiltration (UF)
9
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 1
Day 24
Koomans HA. Body fluid dynamics during dialysis
InZoccali (ed). Clinical hypertension in
Nephrology. Contr.Nephrol. 1996119173-181
10
Extracellular volume (ECV) and blood volume
(BV) in chronic renal failure
BV cannot be increased indefinitely
Koomans HA et al. Kidney Int. 1986 30730-735
11
MAP and ECFV
The determinant of BP is the blood volume
Koomans HA et al. Kidney Int. 1986 30730-735
12
Predialytic Extracellular Volume (ECV) and Mean
Arterial Pressure (MAP) during the course of HD
MAP
ECV
Charra B. et al. Am.J.Kidney Dis. 199832720-724
13
Effects of ultrafiltration on MAP, HR, PV, and COP
(Colloid Osmotic Pressure)
Koomans HA et al. Kidney Int. 1986 30730-735
14
HEMODYNAMIC CHANGES DURING EXTRACORPOREAL
THERAPIESin normotensive pts
15

• Hypertension is common in dialysed patients
• - at pre-dialysis state gt80,
• - in patients with hemodialysis gt60,
• in those with peritoneal dialysis gt30
• 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.
16
Increased cardiovascular mortality in end stage
renal failure
100
ESRD
10
1
mortality/year ()
0,1
cardiovascular
unselected population
0,01
25-34
55-64
35-44
45-54
65-74
75-84
gt 84
Age group (year)


Sarnak Levey 2000
17
Impact of BP on Survival in Hemodialysis
Patients depending on the presence of IHD
SBP lt160 mm Hg
SBP gt160 mm Hg
SBP gt160 mm Hg
SBP lt160 mm Hg
Kimura G. et al. Am.J.Hypertens.199691006-1012
18

• 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 .

19
DM
Life expectancy of hemodialysed
diabetics (prospective study in Germany)
Koch, NDT (1997) 12 2603
20

• In patients on hemodialysis, hypertension has
  been
• associated with
• stroke,
• MI,
• CHF,
• ventricular arrhythmias and
• progression of atherosclerosis

21
Increased rate of vascular calcification in ESRD
Normal renal function
ESRD
JACC, 2002
22
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
23
Systolic blood pressure and cardiovascular
mortality in dialysed patients
R I SK
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.
24
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 (CRPlt) -
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
25
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
lt160 1.00 1.00 1.00
160-199 0.80 0.85 1.67
200-239 1.16 0.97 3.14
gt240 0.87 0.72 4.60
?
Liu Y et al. JAMA 2004 291451-459.
26
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 (CRPlt) -
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
27
Anemia Is a Mortality MultiplierDM/CHF Have The
Same Mortality Risk As Chr. Kidney Disease/Anemia
7.3
8.0
6.3
7.0
6.0
6.0
4.7
4.6
5.0
4.0
3.7
3.7
Relative Risk
3.6
4.0
2.9
2.4
2.4
3.0
2.0
2.0
1.5
2.0
1.0
1.0
0.0
None
DM only
CKD only
CHF only
Anemia only
DM/CHF only
DM/CKD only
CHF/CKD only
DM/Anemia only
CHF/Anemia only
CKD/Anemia only
DM/CHF/CKD only
DM/CHF/Anemia only
DM/CHF/CKD/Anemia
DM/CKD/Anemia only
CHF/CKD/Anemia only
Collins, AJ. Adv Stud in Med. 20033(3C)S14-S17.
28
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 (CRPlt) -
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
29
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 KO mice Metastatic
soft tissue, cardiovascular (intra-arterial)
calcification Clinic Decreased se. conc. in
ESRD
Inhibitor of Ca X PO4 precipitation, 50 of
precipitation inhibitory effect of serum
30
Serum fetuin-A (AHSG) levels as a prognostic
marker of all-cause and cardiovascular mortality
in ESRD
Cardiovascular mortality
All-cause mortality
Proportion surviving ()
Proportion surviving ()
Follow-up (months)
Follow-up (months)
Ketteler et al., Lancet, 2003
31
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 (CRPlt) -
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
32
Obesity and ESRD
Survival of the chronically dialysed obese
patients is longer than that of non-obese ones
(But! mostly in Afro-Americans) Obese patients
are frequently under-dialysed (!?) After renal
transplantation the survival of grafts are
shorter in obese than in non-obes patients.
33
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
34
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
35
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.
36
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.

37
- 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.
38
Hypertension Severity Index (HSI)
HSI score Systolic BP (mmHg) Diastolic BP
(mmHg) 0 lt 150 lt 90
1 150-159 90-99 2 160-179 100-109
3 gt 179 gt 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.
39
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.
40
Target blood pressure in dialysed hypertensive
patients
Causal measurement, mercury sphygmomanometer
Dialysed elderly patient lt150/90 mm
Hg Dialysed young patient or Dialysed patient
with T2DM lt120/80 mm
Hg Hypertensive nephropathy
120-130/75-80 mm Hg Proteinuria (gt1 g/day)
lt125/75 mm Hg Renovascular
hypertension lt130/85 mm Hg ABPM
daytime average lt 135/85 mm Hg, nighttime
average lt 120/80 mm Hg.
Henrich WL, Mailloux LU. Hypertension in dialysis
patients. Rose B. UpToDate online 11.3, 2004,
http//www.uptodate.com
41
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 lt 135/85 mmHg
- by night lt 120/80 mmHg. CAUTION! Very low
systolic blood pressure (lt110 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
42
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.
43
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.
44
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.
45
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.

46
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

47
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

48
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 patients 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.
49
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

50
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.
51
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

52
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.
53
Pharmacological treatment of hypertension in
dialyzed patients
Suggested use of antihypertensive drugs in
hemodialysis patients (which drug - when)
Drugs Compelling indication
Specific side-effects Special
precautions ACE inhibitors LVH, CHF, DM,
Anaphylactoid reactions with

AN69 dialyzer DHP-CCB
CHD Non-DHP-CCB CHD

No comb. with BBL BBL
CHD Excessive
bradycardia No comb with

with liposoluble compounds
non-DHP-CCB Centrally act. none
Post-dialysis rebound
Avoid agents
with
methyldopa ABL
Dyslipidemia
Severe hypotension
Insulin
resistance Direct
Hypertensive
In hospital
use vasodilators crisis
54
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
P r o g r e s s i o n o f k i d n e y
d i s e a s e
55
Some remarks for antihypertensive drug classes

• ACE-inhibitors
• effective and well tolerated
• reduce mortality also of dialysed patients (age
  lt 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

56
Clinical Endpoint Data for ESRD in Type 2
Diabetes with ACE Inhibitors

• Endpoints
  Studied
• ACE Inhibitor Trials
• in Type 2 Diabetics Total
  Reduction of Reduction of Reduction in Risk
  with gt1 Yr Follow-up Sample
  Proteinuria Fall in GFR of ESRD
• Ravid et al Ann Int Med 1993 94
  YES YES NO
• Lebovitz et al Kid Int 1994 121
  YES YES NO Bakris et al Kid Int
  1996 52 YES
  YES NO
• Ahmad et al Diab Care 1996 103
  YES YES NO
• Nielsen et al Diabetes 1997 43
  YES YES NO
• UKPDS et al Br Med J 1998 758
  YES YES NO
• Fogari et al J Hum Hypertens 1999 107
  YES YES NO
• ABCD Diab Care 2000 470
  YES YES NO
• Ruggenenti et al (REIN) 352 (27)
  NO YES YES
• Am J Kid Dis 2000 MICRO-HOPE Lancet 2000
  3577 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)
57
Main outcomes in patients with renal
insufficiency (serum creatinine ? 1.4 mg/dl)
Prim. outcome
MI
All Placebo Ramipril
Mann, Gerstein, Yusuf, Ann Int Med,
2001134629-36
lt 1.4
?1.4
Events (per 1000 pt-yrs)
lt 1.4
? 1.4
All Death
CV Death
lt 1.4
? 1.4
lt 1.4
? 1.4
58
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.

59
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

60
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.

61
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.
62
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

63
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

64
RENAAL Primary Components
ESRD
Risk Reduction 28
P
p0.002
with event
L
Doubling of Serum Creatinine
Risk Reduction 25
p0.006
Months
P ( CT)
762
715
610
347
42
L ( CT)
751
714
625
375
69
with event
ESRD or Death
Risk Reduction 20
p0.010
P
with event
L
Months
762
689
554
295
P ( CT)
36
L ( CT)
751
692
583
329
52
Months
P ( CT)
762
715
610
347
42
L ( CT)
751
714
625
375
69
Brenner BM et al New Engl J Med
2001345(12)861-869.
65
RENAALFirst Hospitalization for Heart Failure
Risk Reduction 32 p0.005
P
with event
L
0
12
24
36
48
Months
P (CT)
762
685
616
375
53
L (CT)
751
701
637
388
74
Brenner BM et al New Engl J Med
2001345(12)861-869.
66
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 (51kidney, 50
  liver), therefore no
• need to reduce the dose

67
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

68
Antihypertensive drugs in dialysis
patients Summary (when which drug)
Cliniucal situation Drugs of choice
Not recommended CHF
ACEi, ARB, BBL
- Post-MI ACEi, BBL
Dir. vasodil. LVH diast.dysf.
BBL, dilti., verap. Dir.
vasodil., a1BL COPD
ACEi, ARB, CCB BBL CHD
BBL, ACEi, CCB
ARB

Locatelli F. et al. Nephrol. Dial. Transoléant.
2004 191058-1068
69
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
Rectors 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
Kaplans 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 Rectors 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 Experts
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
70
How well are we doing?
71
Guidelines And Practice (GAP) Study Association
of patient characteristics with uncontrolled
systolic BP
200 family physicians 17,000 patients
Decreases ? ? Increases
72
Guidelines And Practice (GAP) Study Association
of patient characteristics with uncontrolled
diastolic BP
Decreases ? ? Increases
73
Guidelines And Practice (GAP) StudyAssociation
of patient characteristics with the physician
being less stringent than guidelines compared
to the physician being more stringent than
guidelines
increases
decreases
16x
?
74
We should do much better..
75
THANKS FOR YOUR ATTENTION
76
Next ESH Summer School September 24 30,
2005 In Visegrád, Hungary
77
THANK YOU FOR YOUR ATTENION
78
Additional slides
79
Brescia, University Campus
80
Thank you for your attention
81
Role of Hypertension in the Pathogenesis of ESRD

82
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 lt90 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 291844-50.
83
Hypertension and Kidney FailureA 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

84
Hypertension and Kidney FailureA Vitious Circle
II.

• Na excretion gt extracellular fluid
  volume lt
• Cardiac output lt
• Vasopressor (RAAS, NA, VA, ET)
  activity increases
• Vasodilator tone decreases
  (renomedullary lipidek, kinins, vasodilator
  prostaglandins)
• Activity of endogenous inhibitors of
  NO synthesis increases (asymmetric
  dimethyl-arginin)

85
Etiology of hypertension in chr.
parenchymal renal disease

• Hypernatraemia, hypervolaemia
• RAAS activation
• Ratio of vasoconstrictor / vasodilator
  substances
• changes (endothelin-1lt / NOgt)
• PTH level lt
• Number of nephrons gt
• Progression of hypertensive disease
• Erythropoietin therapy

86
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
87
THE EFFECT OF HEMODIALYSIS ON LV FUNCTION
YES
YES
NO
88
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
89
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
lt160 1.00 1.00 1.00
160-199 0.74 0.76 1.23
200-239 0.74 0.71 2.33
gt240 0.71 0.62 3.22
Liu Y et al. JAMA 2004 291451-459.
90
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
91
A CV Continuum the Beginning and the EndFrom
High Blood Pressure to Renal and Cardiac Damage
Normotensive
H y p e r t e n s i o n
Higher
Decline in Glomerular Filtration Rate
Vascular Hypertrophy
Health Status/QOL
Left Ventricular Dysfunction
Renal Impairment
Stroke
Heart Failure
Kidney Failure
Lower
HD
Death
Time, years
Dzau V, Braunwald E. Am Heart J.
199112112441263.
92
Role of ProteinuriaPercentage of patients having
a cardiovascular event (and hazard ratio) per
decile of UA / CR (mg/mmol)
Decile of UA / CR lt0.25 0.25-0.41 0.41-0.59 0.59-0.82 0.82-1.16
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 2003139901-6.
93
Features of antihypertensive therapy in dialysed
patients
ARB
Organ-protection
CCB
ACE-i
and /or
BBL
Decrease the activity of sympathetic nervous
system
Decrease risk factors
Centrally acting drugs
vasodilator
94
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.
95
Effects of proteinuria on stroke and on CHD in
T2DM
A U-Prot lt150 mg/L
B U-Prot 150300 mg/L
C U-Prot gt300 mg/L
40
P lt0.001
30
Survival
Incidence ()
20
10
0
Stroke
CHD Events
U-Prot urinary protein concentration.
Miettinen H et al. Stroke. 19962720332039.