Eberhard Ritz Heidelberg (Germany) Cardiovascular problems on hemodialysis – current deficits and potential improvements

Eberhard Ritz Heidelberg (Germany)

Cardiovascular problems on hemodialysis –

current deficits and potential improvements

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

Ultrafiltration rate and treatment time –

impact on mortality (DOPPS study)

Saran, Kidn.Internat.(2006) 69:1222

ultrafiltration rate treatment time

Only observational evidence, but …

odds ratio intradialytic hypotension

1.3 (p=0.045)

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


Underlying cardiac disease- coronary heart disease vs.- cardiomyopathy

New therapeutic targets- salt and salt mediated hormones- sympathetic activity


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

coronary heart disease 9 % 6 %

other cardiac causes 35 % 33 %(sudden death 26%; heart failure 6%; other cardiac 3%)

stroke 6 % 10 %

non-cardiovascular 50 % 51%

4D study USRDS

Wanner, New Engl J Med (2005) 353:238

Higher mortality in CKD patients with diastolic (EF>45%) vs systolic heart failure

(Digitalis Investigation Group Trial)

Ahmed, Am.J.Cardiol.(2007) 99: 393

systolic malfunction

diastolic malfunction

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)

Aoki, Kidn.Internat.(2005) 67:333

dilatedcardiomyopathy

idiopathic

hemodialysis

< 30%

> 30%

fibrosisarea

Cardiovascular risk in chronic kidney disease

vascular disease cardiomyopathy

• atherosclerosis (plaques)

• arteriosclerosis (arterial stiffening)

• inappropriate (LV)

hypertrophy

• interstitial fibrosis

• microvessel

disease (wall thickening of postcoronary

arteries,

capillary deficit)

systolic dysfunction, diastolic dysfunction,electrical instability


Underlying cardiac disease

Novel pathogenetic pathways and therapeutic targets- salt and salt mediated hormones- (phosphate- vitamin D)- sympathetic activity



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

Stella, J.Intern.Med.(2008) 263:274

Correlation between ouabain (OLF) and left

ventricular abnormalities in dialysis patients

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+

Gross, Am.J.Kidn.Dis (2005) 46:94

Blood pressure : Spironolactone 142→131 mmHg Placebo 146→142 mmHg

Quartiles of plasma aldosterone concentrations within the normal range –

progressively higher hazard ratio for CV death in 3153 coronary patientsLURIC 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

Kidney International (2006) 70: 1905

in dialysis patients: beta blockers 22.9% in USA, 29.5% worldwide (DOPPS I and II)

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



New therapeutic targets- salt and salt mediated hormones- phosphate- vitamin D- sympathetic activity



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 %

adjusted rel.risk

death hospitalisation

physician diagnosed 1.23 1.11

patient diagnosed !! 1.48 1.15

(“so down in the dumps”)

Lopes, Kidn.Intern. (2002) 62:199

Depression and mortalityDOPPS

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)

depression independent factor predicting higher

cardiovascular mortality

Ferketich, Arch Int Med (2000) 160:1261Pratt Circulation (1996) 94:3123Yusuf, Lancet (2004) 364:953

Frasure-Smith, Circulation (1995) 91:999Glassman Am J Psychiatr (1998) 155:4

MelancholieAlbrecht 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 risklinked 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 %

estimated overall prevalence in HD patients

→ 21 - 47%

prevalence in general population

→ 2 - 4%

Kimmel,Am.J.Med.(1989)86:308

Pressman, Kidn.Intern.(1993) 43:1134

Young, New Engl.J.med.(1993) 328:1230

Sleep-apnea –reduced survival

Yaggi, New Engl J Med (2005) 353:2034

Survival advantage with treatment ?

McEvoy, Thorax, e-pub Feb12th

multicenter open label

randomized controlled trial

144 smokers

oxygen vs support ventilation

adj.hazard ratio 0.63 (0.4-0.99) p=0.045

cumulativesurvival

month

average nocturnaloxygen saturation

SaO2

Nocturnal episodes of arterial oxygen desaturation predict cumulative CV events and survival in HD patients

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

Insomnia

obstructiv

e sleep apnea

rest

less

legs

Epwoth s

leep

ines

s sc

ale

Narco

lepsy

slee

pwalki

ng

nightm

ares

behav

iour

disord

er

In hamsters disruption of a regulatory protein entraining

circadian rhythmcompared to controls

causes- cardiomyopathy

-renal disease

Massontrichrome

Siriusred

Martino, Am.J.Physiol.(2008) 294:R1675



New therapeutic targets- salt and salt mediated hormones- (phosphate- vitamin D) sympathetic activity


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

“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”.

Nature Medicine (2002) 8:1066

Why did you rob the bank ?

Because that’s where the money is!

Which topics to study?

miR-21, -133, -150, -195, -214 → cardiomyocyte hypertrophymiR-1, miR-133 → arrhythmia

miR-21, miR-195 apoptosismiR-208 myosin content ↑ and contractility ↑

miR-21, miR-29 cardiac fibrosismiR-126 neoangiogenesis

van Rooij, Circulation Res. (2008) 103: 919

MicroRNA in the heart

Endothelial to mesenchymal cell transition involved in myocardial fibrosis of mice with increased afterload

TGFβ-SMAD colocalisation in capillary endothelial cells

Zeisberg, Nature Medicine (2007) 13:952

TGFβ expression coexpressionof TGFβ (red) +

p-SMAD2/3(green)

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

sham-op 1.5 ± 0.6 3706 ± 571 5.16 ± 0.97

UNX 2.1 ± 0.4 2709 ± 407 7.00 ± 2.02

UNX + 1.3 ± 0.3 3776 ± 534 4.85 ± 0.68Tempol

Vvinterstitialcells (%)

Lvcapillary length

density (mm/mm3)

IMT (µ)intramyocardial

arteries

fibrosis capillarydeficit

arterialthickening

reversal ofoxydative stress

Piecha, J.Hypertens.(2008) 26: 2220

In the long term –

hypertension powerful predictor of mortality on hemodialysis

Charra, Kidney International (1992) 41:1286

mean arterial pressure % patients surviving

years

5 10 15 20

< 99 mm Hg 93 85 67 53

> 99 mm Hg 81 65 43 -

Sleight P. ESH/ISH Meeting, Berlin 2008; ESC Meeting, Munich 2008

0.20.2 0.40.4 0.60.6 0.80.8 1.01.0 1.21.2 HR(95% CI)HR(95% CI)

Changes SBPChanges SBP Reduced RiskReduced Risk Increased RiskIncreased Risk• HRHR (95%CI)(95%CI) p-value (changes SBP as continuous)p-value (changes SBP as continuous)

p=0.0066p=0.0066Q1: baseline SBP <= 130Q1: baseline SBP <= 130

•T1: <= -9.17T1: <= -9.17 •11

•T2: > -9.17 & <= 0.22T2: > -9.17 & <= 0.22 •1.21.2 •( 1.04 , 1.4 )( 1.04 , 1.4 )

•T3: > 0.22T3: > 0.22 •1.191.19 •( 1.02 , 1.38 )( 1.02 , 1.38 )

Q2: baseline SBP > 130 & <= 142Q2: baseline SBP > 130 & <= 142 p=0.0004p=0.0004

•T1: <= 0T1: <= 0 •11

•T2: > 0 & <= 8.36T2: > 0 & <= 8.36 •0.890.89 •( 0.76 , 1.04 )( 0.76 , 1.04 )

•T3: > 8.36T3: > 8.36 •0.810.81 •( 0.69 , 0.95 )( 0.69 , 0.95 )

Q3: baseline SBP > 142 & <= 154Q3: baseline SBP > 142 & <= 154 p<0.0001p<0.0001

•T1: <= 5.5T1: <= 5.5 •11

•T2: > 5.5 & <= 14T2: > 5.5 & <= 14 •0.770.77 •( 0.67 , 0.89 )( 0.67 , 0.89 )

•T3: > 14T3: > 14 •0.590.59 •( 0.5 , 0.69 )( 0.5 , 0.69 )

Q4: baseline SBP > 154Q4: baseline SBP > 154 p<0.0001p<0.0001

•T1: <= 11.92T1: <= 11.92 •11

•T2: > 11.92 & <= 21.71T2: > 11.92 & <= 21.71 •0.720.72 •( 0.63 , 0.82 )( 0.63 , 0.82 )

•T3: > 21.71T3: > 21.71 •0.570.57 •( 0.5 , 0.66 )( 0.5 , 0.66 )

Primary endpoint in ON TARGET study:

adjusted risk according to tertiles of systolic baseline pressure

risk increase

risk decrease

risk decrease

risk decrease

Target blood pressure : the lower,the better ?

Diastolic BP < 70mmHg : more frequently de novo MI, but not stroke

Messerli, Ann.Int.Med.(2006) 144:884

MI

stroke

Blood-pressure amplitude and mortality Type 2 diabetic nephropathy

(IDNT study)

Berl, J.Am.Soc.Nephrol.(2005) 16:2170

Greater blood pressure amplitude (loss of vascular elasticity)

higher overall mortality

Diastolic blood pressure and myocardial infarction – type 2 diabetic nephropathy

(IDNT study)

Berl., J.Am.Soc.Nephrol.(2005) 16:2170

lower diastolic blood pressure

higher incidence of MI

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.

Heerspink, Lancet (2009) 373: 1009

Cardiovascular events in HD patients-effect of antihypertensive treatment –

metaanalysis

All cause mortality and CV mortality in HD patients-effect of antihypertensive treatment –

metaanalysis


Prevention of stroke Calcium channel blockers vs ARBs

Wang ,Hypertension (2007)50: 181

Not all antihypertensives equally effective on different endpoints

Communist view

One blood pressure

fits all

define in observational studies

which blood pressure is optimal for

which patient (comorbid conditions)

Juan GrisRetratto de Josette

1916

Thank you

for your

attention

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 patientsMetaanalysis

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

Documents

Eberhard Ritz Heidelberg (Germany) Cardiovascular problems on hemodialysis – current deficits and potential improvements