Download Cardiovascular problems on hemodialysis

Cardiovascular problems on hemodialysis –
current deficits and potential improvements
Eberhard Ritz
Heidelberg (Germany)
Epidemiological facts
Underlying cardiac disease
- coronary heart disease
- cardiomyopathy
New therapeutic targets
- salt and salt mediated hormones
- sympathetic activity
Neglected cardiovascular risks
- depression
- sleep apnea
- disrupted biorhythm
Attractive areas for future investigation
-
micro-RNA – arrhythmia/cardiac fibrosis
salt and marinobufagenin
sympathetic overactivity and beta blockers
oxydative stress
Only observational evidence, but …
Ultrafiltration rate and treatment time –
impact on mortality
(DOPPS study)
ultrafiltration rate
treatment time
odds ratio
intradialytic hypotension
1.3 (p=0.045)
Saran, Kidn.Internat.(2006) 69:1222
Diuretic use
(DOPPS study)
rel.risk
diuretic vs no diuretic
all cause mortality
0.93
p=0.12
cardiac mortality
0.86
p<0.03
interdialytic weight gain > 5.7%
0.51
p<0.0001
hypotensive episodes
0.55
p<0.006
Bragg-Gresham, Am.J.Kidn.Dis.(2007) 49:426
In the case of dialysis patients, a low normal level of ECV is maintained
by the powerful tool of ultrafiltration,
which if properly used along with
moderate dietary sodium restriction and
maintenance of natriuresis by diuretics,
are the only proven method of
controlling blood pressure in the hemodialysis population.
Scribner, Trans. Am. Soc. Artif. Intern. Organs (1960) 6:114
Epidemiological facts
Underlying cardiac disease
- coronary heart disease vs.
- cardiomyopathy
New therapeutic targets
- salt and salt mediated hormones
- sympathetic activity
Neglected cardiovascular risks
- depression
- sleep apnea
- disrupted biorhythm
Attractive areas for future investigation
- micro-RNA – arhythmia/cardiac fibrosis
- salt and marinobufagenin
- sympathetic overactivity and beta blockers
- oxydative stress
Causes of death in dialysis patients
4D study
coronary heart disease
other cardiac causes
USRDS
9%
35 %
6%
33 %
(sudden death 26%; heart failure 6%; other cardiac 3%)
stroke
non-cardiovascular
6%
50 %
Wanner, New Engl J Med (2005) 353:238
10 %
51%
Higher mortality in CKD patients with
diastolic (EF>45%) vs systolic heart failure
(Digitalis Investigation Group Trial)
systolic malfunction
diastolic malfunction
Ahmed, Am.J.Cardiol.(2007) 99: 393
Myocardial changes in patients
with renal failure
normal morphology
morphology of the myocardium of a patient
with chronic renal failure
Consequences of cardiac
fibrosis on heart function
• reduced LV compliance
• arrhythmia
fibrous tissue encircling cardiomyocytes has high
electrical resistance
local delay of the spreading front of action potential
favours “reentry” type atrial and ventricular arrhythmias
Cardiac fibrosis –
most powerful predictor of survival in HD patients
(endomyocardial biopsies)
dilated
cardiomyopathy
idiopathic
< 30%
fibrosis
area
> 30%
Aoki, Kidn.Internat.(2005) 67:333
hemodialysis
Cardiovascular risk in chronic kidney disease
vascular disease
• atherosclerosis
(plaques)
• arteriosclerosis
(arterial stiffening)
cardiomyopathy
• inappropriate (LV)
hypertrophy
• interstitial fibrosis
• microvessel
disease
(wall thickening of postcoronary
arteries,
capillary deficit)
systolic dysfunction, diastolic dysfunction,electrical instability
Epidemiological facts
Underlying cardiac disease
Novel pathogenetic pathways and
therapeutic targets
-
salt and salt mediated hormones
(phosphate
vitamin D)
sympathetic activity
Neglected cardiovascular risks
- depression
- sleep apnea
- disrupted biorhythm
Attractive areas for future investigation
- micro-RNA – arhythmia/cardiac fibrosis
- salt and marinobufagenin
- sympathetic overactivity and beta blockers
- oxydative stress
Adverse effects of high salt
-
not only high blood pressure and hypervolemia, but also
-
blood pressure independent target organ damage
(cardiovascular damage, progression of CKD)
Frohlich, Hypertension (2007) 50:161
Matavelli, Journal of Physiology (Heart Circulation Physiol.) (2007) 292:h814
Sanders, Hypertension (2004)143:142
Marinobufagenin
cardiotonic steroid
inhibitor of Na+ K+ ATP’ase
- concentration correlated to cardiomyopathy
in subtotally nephrectomised rats
- cardiomyopathy reproduced by
administration of marinobufagenin
- cardiomyopathy prevented by
neutralizing antibodies to marinobufagenin
- deserves investigation in dialsysis patients
Kennedy, Hypertension (2006) 47:488
Federova, American Journal Physiology (Renal Physiology) (2009) e-pub
Correlation between ouabain (OLF) and left
ventricular abnormalities in dialysis patients
Stella, J.Intern.Med.(2008) 263:274
Antagonist: Rostafuroxin ?
Therapeutic targets and potential future approaches
#
reduction of salt intake (recommended by Scribner, but sadly forgotten today)
Ritz, Blood Purification (2006) 24:63
#
lowering of serum Na concentration (physicochemical activity)
by adjusting dialysate Na concentration ?
even minor increases of sodium concentration in serum or cerebrospinal fluid
stimulate pressor-mechanisms and increases the release of cardiotonic steroids
Huang, Hypertension (2007) 49:1315
Newly diagnosed essential
hypertension :
diastolic blood pressure
and
plasma sodium
in different quartiles of
ouabain
Manunta, J.Hypertens.(2007) 26:914
Plasma sodium concentration stiffens human vascular
endothelium in vitro –
in the presence of aldosterone,
abrogated by eplerenone
Oberleithner, Proc.Natl.Acad Sci USA (2007) 104:16281
In presence of activated mineralocorticoid receptor
NO production by endothelial cells lowered
by sodium
Wildling, Pflügers Arch. (2008)e-pub Sept 3rd
Therapeutic targets and potential future approaches
#
reduction of salt intake
Ritz, Blood Purification (2006) 24:63
#
lowering of serum Na concentration
by adjusting dialysate Na concentration ?
Huang, Hypertension (2007) 49:1315
#
ouabain antagonist Rostafuroxin
Ferrari, American Journal of Physiology (Regul. Integr. Comp. Physiol.) (2006) 290:r529
#
aldosterone antagonist Spironolactone
Bomback, Nat.Clin.Pract.Nephrol.(2009) 5:74
Lowering of blood pressure by 50 mg Spironolactone
in anuric hemodialysis patients –
no change in S-K+
Blood pressure : Spironolactone 142→131 mmHg
Placebo
146→142 mmHg
Gross, Am.J.Kidn.Dis (2005) 46:94
Quartiles of plasma aldosterone concentrations within the normal range –
progressively higher hazard ratio for CV death in 3153 coronary patients
LURIC study
Tomatschik, submitted
Nature Clin.Practice Nephrol. (2009) 5: 74
Sympathetic overactivity
(well investigated, few practical consequences)
documented in earliest stage of CKD
Klein, J.Am.Soc.Nephrol. (2001) 12:2427
pronounced in endstage kidney disease
Converse, New Engl.J.Med. (1992) 327:1912
caused by increased afferent signals emanating from the
kidney
Ye, Kidney International (1997) 51:722
in dialysis patients: beta blockers 22.9% in USA, 29.5% worldwide (DOPPS I and II)
Kidney International (2006) 70: 1905
like the prophet in the desert
Phagocytic cells produce catecholamines
amplifying inflammatory reactions
Flierl, Nature (2007) 449:721
PLoS ONE (2009) 4:e4414
benefit beyond blood pressure and antiarrhythmic activity?
LPS stimulates production of noradrenaline
by macrophages and neutrophils
Flierl, Nature (2007) 449:721
Renalase –
normally detected in blood or urine but
absent if renal function is lost
Li, Circulation (2008) 117:1277
Epidemiological facts
Underlying cardiac disease
New therapeutic targets
-
salt and salt mediated hormones
phosphate
vitamin D
sympathetic activity
Neglected cardiovascular risks
- depression
- sleep apnea
- disrupted biorhythm
Attractive areas for future investigation
- micro-RNA – arhythmia/cardiac fibrosis
- salt and marinobufagenin
- sympathetic overactivity and beta blockers
- oxydative stress
Science’s greatest advances occur on
the frontiers, at the interface between
ignorance and knowledge, where the
most profound questions are posed
Science (2005) 309: 76
Depression and adverse outcomes on HD
(DOPPS study)
prevalence of depression ~ 20 %
physician diagnosed
patient diagnosed !!
(“so down in the dumps”)
adjusted rel.risk
death
hospitalisation
1.23
1.11
1.48
1.15
Lopes, Kidn.Intern. (2002) 62:199
Depression and mortality
DOPPS
How often have you felt :
“So down in the dump“
“Downhearted and blue“
Lopes, Kidn.Intern. (2002) 62:199
Depressive syndromes –
predict later appearance of cardiovascular disease
risk higher by factor 1.7 – 4.5
(e.g. NHANES and INTERHEART studies)
Ferketich, Arch Int Med (2000) 160:1261
Pratt Circulation (1996) 94:3123
Yusuf, Lancet (2004) 364:953
depression independent factor predicting higher
cardiovascular mortality
Frasure-Smith, Circulation (1995) 91:999
Glassman Am J Psychiatr (1998) 155:4
Melancholie
Albrecht Dürer
1471-1528
In patients with cardiovascular disease
16 – 23 % major depression requiring
intervention (DSM-III-R or DSM IV)
Musselman, Arch Gen Psychiatr (1998) 55:580
Depression and cardiovascular risk
linked to:
•
•
•
•
•
autonomic imbalance
hypercorticism
insulin resistance
microinflammation
…
Everson-Rose, Diabetes Care (2004) 27:2856
Etanercept in psoriasis
improved clinical outcomes and less depression
(Double-blind placebo controlled randomized phase III trial)
Türing, Lancet (2006) 307:29
Depression provoked by interferon-α therapy in patients
with malignancy
successfully treated with the antidepressant paroxetine
Musselman, New Engl.J.Med. (2001) 344:961
Less depression – the explanation ?
for the positive effect of :
# spirituality
Finkelstein, Nephrol.Dial.Transpl.(2007) 22:2432
# and support provided by care givers
Tong, Nephrol.Dial.Transplant. (2008) 23:3060
► on quality of life of patients on renal
replacement therapy?
Sleep quality score correlated to mortality
(DOPPS study)
Elder, Nephrol.Dial.Transplant.(2008) 23:998
Sleep apnea in HD patients
in symptomatic HD patients (restless sleep, morning
headaches, daytime sleepiness, personality changes)
→ frequency 73 %
Kimmel,Am.J.Med.(1989)86:308
estimated overall prevalence in HD patients
→ 21 - 47%
Pressman, Kidn.Intern.(1993) 43:1134
prevalence in general population
→ 2 - 4%
Young, New Engl.J.med.(1993) 328:1230
Sleep-apnea –
reduced survival
Yaggi, New Engl J Med (2005) 353:2034
Survival advantage with treatment ?
multicenter open label
randomized controlled trial
144 smokers
oxygen vs support ventilation
adj.hazard ratio 0.63 (0.4-0.99) p=0.045
McEvoy, Thorax, e-pub Feb12th
Nocturnal episodes of arterial oxygen desaturation predict
cumulative CV events and survival in HD patients
cumulative
survival
average nocturnal
oxygen saturation
SaO2
month
Zoccali,J.Am.Soc.Nephrol.(2002)13:729
Daily nighttime dialysis –
impact on neurological and cardiovascular functions
•
Chan C.T.,Harvey P.J.,Picton P.,Pierratos A.,Miller J.A.,Floras J.S.
Short-term blood pressure, noradrenergic and vascular effects of nocturnal
home hemodialysis
Hypertension (2003) 42:925
•
Chan C.T.,Hanly P., Gabor J., Picton P., Pierratos A., Floras J.S.
Impact of nocturnal hemodialysis on variablity of heart rate and duration of
hypoxemia during sleep
Kidney Int. (2004) 65:661
•
Chan C.T.,Jain V., Picton P., Pierratos A., Floras J.S.
Nocturnal hemodialysis increases arterial baroreflex sensitivity and compliance
and normalizes blood pressure of hypertensive patients with endstage renal
disease
Kidney Int. (2005) 68: 338
sleep apnea a novel index of dialysis adequacy?
in the 4D study 70% of sudden death during nighttime !
Improvement of sleep-apnea with daily
hemodialysis at nighttime (NHD)
Hanly, New Engl..J.Med.(2001) 344:102
New Engl.J.Med.(2005)353:2070
Frequeny of sleeping disorders in dialysis patients
Merlino,Nephrol.Dial.Transpl.(2006) 21:184
Masson
trichrome
In hamsters disruption of a
regulatory protein entraining
circadian rhythm
compared to controls
causes
- cardiomyopathy
-renal disease
Sirius
red
Martino,
Am.J.Physiol.(2008) 294:R1675
Epidemiological facts
Underlying cardiac disease
New therapeutic targets
- salt and salt mediated hormones
- (phosphate
- vitamin D)
sympathetic activity
Neglected cardiovascular risks
- depression
- sleep apnea
- disrupted biorhythm
Attractive areas for future investigation
- micro-RNA – arhythmia/cardiac fibrosis
- salt and marinobufagenin
- sympathetic overactivity and beta blockers
- oxydative stress
- target blodd pressure
Ich schätze den Mann der so schreibt wie es
einmal Mode werden wird und nicht jenen,
der so schreibt wie es Mode ist
I respect the man who writes what will be
the fashion of tomorrow,
not the man who writes what is
the fashion of today
Lichtenberg G.C.,
1742-1799
Nature Medicine (2002) 8:1066
“Although we have accomplished much, we still have much to do
to improve the lives and the well being of our patients
….we owe them continued research”.
Which topics to study?
Why did you rob the bank ?
Because that’s where the money is!
MicroRNA in the heart
miR-21, -133, -150, -195, -214 → cardiomyocyte hypertrophy
miR-1, miR-133 → arrhythmia
miR-21, miR-195 apoptosis
miR-208 myosin content ↑ and contractility ↑
miR-21, miR-29 cardiac fibrosis
miR-126 neoangiogenesis
van Rooij, Circulation Res. (2008) 103: 919
Endothelial to mesenchymal cell transition
involved in myocardial fibrosis of mice with increased afterload
TGFβ-SMAD colocalisation in capillary endothelial cells
coexpression
of TGFβ (red) +
p-SMAD2/3(green)
Zeisberg, Nature Medicine (2007) 13:952
TGFβ expression
Further attractive areas for future
investigations into pathomechanisms
#
(microRNA and arrhythmia/cardiac fibrosis)
#
marinobufagenin in response to salt loading in CKD and ESRD patients
#
blockade of marinobufagenin action
#
study of aldosterone vasculo- / cardiotoxicty
#
ADMA (not dialysable), homoarginine
#
cardiac metabolism (from glucose to FFA)
#
senescence and its role for cardiovascular tissue in uremia
(telomers,stress)
#
experimental and clinical studies on the reduction of oxydative stress
in cardiomyopathy of CKD
• so far for basic issues
• now urgent clinical issues
- antioxydants
- efficacy of (novel) betablockers
- target blood pressure (observational, not interventional)
- mineralocorticoid receptor blockade
(in anuric patients)
Negative studies lowering homocysteine by
folate in CKD and dialysis patients
Mann, Nephrol.Dial.Transplant.(2008) 23:645
Jamison, JAMA (2007) 298:1163
but studies using alternative antioxydant
medications certainly worthwhile :
why ?
Early onset of uremic cardiomyopathy uninephrectomy (UNX) of ApoE knock-out mice
prevented by reduction of oxydative stress
Vv
interstitial
cells (%)
Lv
capillary length
density (mm/mm3)
IMT (µ)
intramyocardial
arteries
sham-op
1.5 ± 0.6
3706 ± 571
5.16 ± 0.97
UNX
2.1 ± 0.4
2709 ± 407
7.00 ± 2.02
UNX +
Tempol
1.3 ± 0.3
3776 ± 534
4.85 ± 0.68
fibrosis
capillary
deficit
arterial
thickening
reversal of
oxydative stress
Piecha, J.Hypertens.(2008) 26: 2220
In the long term –
hypertension powerful predictor of mortality on hemodialysis
mean arterial pressure
5
% patients surviving
years
10
15
20
< 99 mm Hg
93
85
67
53
> 99 mm Hg
81
65
43
-
Charra, Kidney International (1992) 41:1286
Target blood pressure : the lower,the better ?
Primary endpoint in ON TARGET study:
adjusted risk according to tertiles of systolic baseline pressure
Changes SBP
•
Reduced Risk
HR (95%CI) p-value (changes SBP as continuous)
Q1: baseline SBP <= 130
•T1: <= -9.17
Increased Risk
p=0.0066
•1
•T2: > -9.17
& <=increase
0.22 •1.2 •( 1.04 , 1.4 )
risk
•T3: > 0.22
•1.19 •( 1.02 , 1.38 )
Q2: baseline SBP > 130 & <= 142
•T1: <= 0
p=0.0004
•1
•T2: > 0 & <= 8.36
•0.89 •( 0.76 , 1.04 )
risk decrease
•T3: > 8.36
•0.81 •( 0.69 , 0.95 )
Q3: baseline SBP > 142 & <= 154
•T1: <= 5.5
p<0.0001
•1
•T2: > 5.5 & <= 14
•T3: > 14
•0.77 •( 0.67 , 0.89 )
risk decrease
•0.59 •( 0.5 , 0.69 )
Q4: baseline SBP > 154
p<0.0001
•T1: <= 11.92
•1
•T3: > 21.71
•0.57 •( 0.5 , 0.66 )
risk
•T2: > 11.92
& <= decrease
21.71 •0.72 •( 0.63 , 0.82 )
0.2
0.4
0.6
0.8
1.0
1.2 HR(95% CI)
Sleight P. ESH/ISH Meeting, Berlin 2008; ESC Meeting, Munich 2008
Diastolic BP < 70mmHg :
more frequently de novo MI, but not stroke
MI
stroke
Messerli, Ann.Int.Med.(2006) 144:884
Blood-pressure amplitude and mortality
Type 2 diabetic nephropathy
(IDNT study)
Greater blood pressure amplitude (loss of vascular elasticity)
higher overall mortality
Berl, J.Am.Soc.Nephrol.(2005) 16:2170
Diastolic blood pressure and myocardial infarction –
type 2 diabetic nephropathy
(IDNT study)
lower diastolic blood pressure
higher incidence of MI
Berl., J.Am.Soc.Nephrol.(2005) 16:2170
Patients after MI :
(Valsartan in Myocardial Infarction Study)
Relation between blood pressure and:
cardiovascular death
stroke or
combined cardiovascular events
one blood pressure is not optimal
for all endpoints
Thune, Hypertension 2(008) 51: 48
“Blood pressure: lower is better“
is incorrect
Fonarow, J.Am.Coll.Cardio.(2006) 47:2130
GOBSAT
“Good old boys sitting together and talking“
Sleight P.
Cardiovascular events in HD patientseffect of antihypertensive treatment –
metaanalysis
Heerspink, Lancet (2009) 373: 1009
All cause mortality and CV mortality in HD patientseffect of antihypertensive treatment –
metaanalysis
Heerspink, Lancet (2009) 373: 1009
Not all antihypertensives equally effective on different endpoints
Prevention of stroke
Calcium channel blockers vs ARBs
Wang ,Hypertension (2007)50: 181
Communist view
One blood pressure
fits all
define in observational studies
which blood pressure is optimal for
which patient (comorbid conditions)
Thank you
for your
attention
Juan Gris
Retratto de Josette
1916
Target blood pressure on dialysis
Should we rely on GOBSAT ?
(according to P-Sleight: good old bays sitting and talking)
or
admittedly soft metanalyses of
intervention studies
(e.g. forthcoming metaanalysis in Lancet)
• Renalase
– novel amino-oxydase synthesized as precursor in the kidney
– prorenalase transformed into active renalase by catecholamines or blood
pressure increase
– renalase degrades catecholamines
• Renalase -/- mice are hypertensive and susceptible to ischemic
myocardial damage
• Potential target for interventions
Prevention of stroke and myocardial infarction –
calcium channel blockers vs ARB
►combine !
“not all antihypertensives are created equal”
●
●
Wang, Hypertension (2007) 50: 181
Antihypertensive treatment in hemodialysis patients
Metaanalysis
Heerspink, Lancet (2009) 373: 1009
Body Mass Index and survival on hemodialysis
“Survival of the fattest“
Leavey, Nephrol.Dial.Transplant.(2001) 16: 2386
Body Mass Index and survival on hemodialysis
“Survival of the fattest“
Leavey, Nephrol.Dial.Transplant.(2001) 16: 2386