Current & future management of chronic kidney disease
Chronic Kidney Disease &
Cardiovascular Disease: A clinical
update from KDIGO
Eberhard Ritz
University of Heidelberg
Germany
Rationale
Bidirectional nature of heart-kidney interactions :
primary disorders of one organ causing
secondary dysfunction or injury to the other
new classification reflecting pathophysiology and time frame
in order to speak one common language
Ronco, J.Am.Coll.Cardiol.(2008) 51:1268
Cardiorenal syndrome
(ping-pong, table tennis)
Reduced cardiac output
Reduced net renal perfusion
pressure (?)
Increased protein
synthesis
Cardiac hypertrophy
(compensating hypervolemia)
ROS
ER stress
Chronic heart failure
ANGII, AVP, aldosterone
sympathetic activation
Renal insufficiency
nephrologists being notoriously polite, accepted the sequence :
first heart, then kidney
acute cardiorenal syndrome type 1
heart
kidney
chronic cardiorenal syndrome type 2
heart
kidney
acute
renocardial syndrome type 3
kidney
heart
chronic renocardial syndrome type 4
kidney
heart
systemic
condition
heart
kidney
cardiorenal syndrome type 5
Type 1
acute heart
kidney
Type 1
acute worsening of heart dysfunction
acute kidney injury (AKI)
heart (trigger) :
- hypertensive pulmonary edema with preserved LV systolic function
- acutely decompensated chronic heart failure
- cardiogenic shock
- predominant right ventricular failure
Mebazaa, Crit.Care Med.(2008) 36:S129
kidney (target)
- more severe renal dysfunction when LV function is impaired
Goldberg, Am.Heart J. (2005) 150:330
- AKI independent predictor of 1 year mortality (inflammatory pathways?)
Berl, Clin.J.Am.Soc.Nephrol.(2006) 1:8
- decreased response to diuretic treatment (braking, post-diuretic Na retention)
Ellison, Semin.Nephrol.(1999) 19:581
- risk of hyperkalemia (ACEi;ARB;Spironolactone,Eplerenone)
Verma Curr.Heart Fail.Rep.(2007) 4:183
- aggravation by radiocontrast
McCullough, JACC(2008) 51:1419
Type 1
acute worsening of heart dysfunction
acute kidney injury (AKI)
Assessment of renal (dys)-function :
classic serum marker :
s-creatinine : delayed, confounded, imprecise
novel markers :
s-cystatin C : more costly, not absolutely specific
urine markers ? :
NGAL (neutrophil gelatinase-associated lipocalin)
KIM 1 (kidney injury molecule)
> 0.1 mg/L
Cumulative all cause mortality in
patients with a rise in Cystatin C
within 48h
after hospitalisation for
acute heart failure
> 0.3 mg/L
Lassus, Europ.Heart J.(2011) 31:2791
> 0.5 mg/L
Worsening kidney function
in decompensated heart
failure:
“treat the heart,
don‘t mind the kidney“
Ruggenenti, Europ.Heart J.,(2011) 32:2476
EVEREST trial (Tolvaptan)
Renal impairment in patients with cardiac dysfunction decreased cardiac output or venous congestion ?
RBF renal blood flow
RAP right atrial pressure
Damman, Eur.Heart Fail.(2007) 9:872
Comparison of the prognostic usefulness of N-terminal pro-brain natriuretic
peptide in patients with heart failure with versus without chronic kidney disease
area under the curve
0.81 ±0.03
without CKD
with CKD
Bruch, Am.J.Cardiol.(2008) 102:469
GFR from admission to discharge (% change GFR)
- absence or presence of hemoconcentration
Potential effect of aggressive decongestion on renal function
in patients with decompensated heart failure
Testani, Circulation (2010) 122:265
Type 2
chronic heart
but also heart
kidney
kidney
Type 2
chronic heart dysfunction
progressive chronic kidney disease (CKD)
Chronic congestive heart failure
- even slight decrease of eGFR – significantly increased mortality and
Hillege, Circulation (2006) 113: 671
– marker of severity of vascular disease
- no evidence of simple association between LV ejection fraction
and eGFR or survival
Bhatia, New Engl.J.Med.(2006) 355:260
Renal function (eGFR) –
a predictor of CV death or readmission for CV complications
eGFR
(ml/min/1.73m2)
Hillege, Circulation (2006) 113:671
In contrast to renal function
outcome of heart failure (survival)
virtually independent of ejection fraction
Bhatia, New Engl.J.Med. (2006) 355:260
Type 2
chronic heart dysfunction
progressive chronic kidney disease (CKD)
Chronic congestive heart failure
- balance between vasoconstriction and vasodilatation upset
- of relevance :
vasoconstrictive mediators ↑ (epinephrine, angiotensin, endothelin,…)
reduced sensitivity against, vasodilators ↓ (NO, natriuretic peptides)
EPO ↓
Cras
(Cardiorenal Anemia Syndrome)
impaired renal
function
heart failure
anemia
third partner in crime
Hospitalised patients with heart failure (OPTIMIZE-HF registry)
(in hospital mortality is a function of Hb)
48,612 admissions
259 hospitals
50% pat. Hb < 12.1 g/dl
25% pat. Hb 5-10.7 g/dl
# in hospital mortality :
4.8% vs 3%
# readmission by 90 days
33.1% vs 24.2%
Young, Am.J.Cardiol.(2008) 101:223
Causes of anemia in heart failure
[Cardio-renal anemia syndrome]
Haehling, Contrib.Nephrol.(2011) 171:211
Hämodilution
Hemodilution
Hypervolämie
Hypervolemia
Eingeschränkte
Nierenfunktion
Reduced
renal function
verminderte
EPOproduction
Produktioninder
Niere
Diminished EPO
kidney
EPO
EPOResistenz
resistance
Inflammatorisches
Inflammatory milieuMilieu
RAS Blockade
Poliferationshemmung von
Erythrocyte precursor proliferation inhibited
Erythrozytenvorläufern
gastroinstestinale
Blutung
Gastrointestinal bleeding
RAS blockade treatment
Aspirin,
Aspirin,Antikoagulanzien
anticoagulants
Gestörter
Eisenstoffwechsel
Disturbance
of iron metabolism
gesteigerte
Hepcidinsynthesis
Bildung und
Increased hepcidin
–
Hemmung
der intestinalen
iron availabilty↓
Eisenabsorption
sowie Eisenretention
- Inhibition of intestinal
Fe absorption in
- Retention of Fe in Mø
MØ
Efficacy and safety
of erythropoiesis stimulating agents (ESA) in heart failure
9 randomized controlled trial
(n=747 patients with heart failure)
EMBASE,Medline, Cochrane Library
ESA compared with controls :
significant reduction in CHF related hospitalizations
OR 0.41 (CI 0.24-0.69)
inconclusive effect on mortality
OR 0.60 (CI 0.32-1.11)
improved quality of life,
LV ejection fraction,
lower BNP,
increased exercise tolerance test performance
Lawler, J.Card.Fail. (2010) 16:649
Prevalence of iron deficiency in patients with heart failure
Gender
♀
NYHA
class
NTpro BNP
CRP
p=0.007
Prevalence
NYHA III-IV
p=0.004
Jankowska, Eur.Heart J.,(2010) 31:1872
Prevalence of iron deficiency in patients with heart failure
impact on survival
Cumulative event free survival
Patients without iron deficiency
survival 66.7%
p=0.0002
Patients with iron deficiency
survival 53.6%
Jankowska, Eur.Heart J.,(2010) 31:1872
Iron deficiency:
an ominous sign in patients with systolic chronic heart failure
(prospective observational study)
Hypothesis :
Beyond erythropoiesis iron is involved in numerous
biological processes
Prevalence and consequences :
546 patients with stable congestive heart failure; LVEF 26±7%; NYHA I-IV;
a conservative definition Fe deficiency:
# ferritin<100µg/l or
#100-300µg/l with transferrin saturation < 20%
Iron deficiency 37±4% overall; 32% in patients without anemia and 57% with anemia
Prevalence increased:women, advanced NYHA class,N-terminal pro- BNP,CRP(all p<0.05)
Risk of death (or heart transplantation) HR 1.58 (CI 1.14-2.17)
Jankowska, Europ.Heart J.(2010) 31:1872
Ferric carboxymaltose in patients with
heart failure and iron deficiency
NYHA functional class
Kansas City Cardiomyopathy
questionaire
Anker, New Engl.J.Med.(2009) 361:2436
Ferric carboxymaltose in patients
with heart failure and iron
deficiency
improvement of:
# 6-minute walk test
and
# EQ-5D Visual Analog Scale
Anker,
New Engl.J.Med.(2009) 361:2436
Type 3
acute kidney heart
(mechanisms involved)
Type 3
acute kidney dysfunction
acute cardiac dysfunction
Primary worsening of kidney function:
acute kidney injury (AKI),e.g. ischemia, glomerulonephritis … )
cardiac malfunction, e.g. heart failure, arrhythmia, ischemia …)
AKI (RIFLE criteria : risk; injury; failure; loss; endstage kidney disease)
Bagshaw, Nephrol.Dial.Transplant.(2008) 23:1203
Clinically relevant repercussions on the heart and its consequences :
- fluid overload
- hyperkalemia
- myocardial depressant factors
- pericarditis
- acidemia
- pharmacokinetics !!
- pulmonary edema
- arrhythmia, cardiac arrest
- myocardial contractility ↓
- pulmonary vasoconstriction, arrhythmia
Type 4
chronic kidney
heart
eGFR 60 ml/min/1.73m2
evolution of
CKD
Frequency of chronic kidney disease in the Netherlands
(albuminuria and / or reduced glomerular filtration;GFR)
Stage
GFR
% Population
(glomerular filtration rate)
1
2
3
4
5
>90
0-89
30-59
15-29
<15
Σ
1.3
3.8
5.3
0.1
0.1
10.6 %
de Jong, CJASN (2008) 3:616
10.4%
0.2%
Mild reduction of glomerular filtration rate (GFR)
associated with increased CV mortality
(Hoorn study)
50-75 years
n=631, age, sex and glucose tolerance stratified
follow up 10 years
RR CV death
1.26 per 5 ml/min/1.73m2 decrease of GFR
Henry (2002) Kidney Intern 62: 1402
Mild renal dysfunction associated with incident
coronary disease in young males
23,964 males
follow-up 3.5 yrs
CHD:
>50% narrowing
or MI
Hr 10 !
Pereg, Europ.Heart J.(2008)29:198
Both urinary albumin excretion
and eGFR at baseline
independently predict CV and renal events
Ninomiya, J.Am.Soc.Nephrol.(2009) 20:1813
Risk of CKD (< 60 ml/min/1.73m2)
in 281 hypertensive patients after 13 years follow-up
according to baseline s-creatinine quartiles within normal range
quartile 4
S-Crea >1.2 mg/dl
quartile 3
1.1-1.2 mg/dl
quartile 2
1.0-1.1 mg/dl
quartile 1
< 1 mg/dl
Segura, J.Am.Soc.Nephrol.(2004) 15:1616
Inflammation –
# main driving force for adverse outcomes of CV damage
indicated by biomarkers e.g. CRP, pentraxin3, IL-6 …
Stenvinkel P., Nature Reviews Nephrol.(2012) 8:72
# magnifies the risk of poor outcome,
exacerbates wasting,
triggers vascular calcification …
Carrero, CJASN (2009) 4:S49
Baseline S-P predicts 15 years later coronary
calcium (EB scan) in 3015 healthy young men
(CARDIA study)
Foley,J.Am.Soc.Nephrol.(2009) 20:397
Serum phosphorous and incidence of cardiovascular
disease in the community
(Framingham offspring study)
3368 individuals, follow-up 16.1 years.524 incident CV events
highest vs lowest quartile RR 1.55 (1.16-2.07) p=0.004
Dhingra, Arch.Intern.Med. (2007) 167:879
Increasing CV mortality with progressively higher
serum phosphate within the normal range –
patients with coronary heart disease
Hazard ratio
<2.5
2.5-3.4 3.5-3.9
>4 mg/dl <2.5
2.5-3.4
Tonelli, Circulation (2005) 112: 2627
3.5-3.9
>4 mg/dl
FGF23 (fibroblast growth factor) predicts future
cardiovascular events before HD treatment
Is it phosphate ? Is it FGF23 ?
Seiler, Nephrol.Dial.Transplant (2010) 25:3983
FGF23 (but not klotho)
increased
# LV mass index
and
# ejection fraction
in CKD patients
Faul, J.Clin.Invest.(2011) e-pub Oct 10th
Sham
5/6 nephrectomy
5/6 Nephrectomy in rat
+ FGF23 inhibitor PD173074
partial prevention of altered
heart morphology
(LV mass, wall thickness)
and improved function
(ejection fraction, LV endiastolic diameter)
Faul, J.Clin.Invest.(2011) e-pub Oct 10th
Diastolic BP on treatment and risk of MI –
type 2 diabetic patients with nephropathy
(IDNT study)
lower diastolic BP
higher risk of MI
Berl, J.Am.Soc.Nephrol.(2005) 16:2170
CV disease
control
lower aortic diastolic pressure
Why do renal
patients
tolerate poorly
low diastolic
pressure ?
reduced
coronary
perfusion
(in diastole)
higher LV enddiastolic pressure
Antihypertensive treatment with triple medication
3 drugs in the morning vs 2 (morning) 1 (at bedtime)
Hermida, Hypertension (2008) 51:69
Consequently when aiming for low blood
pressures
two caveats
• do not risk hypotensive episodes
(also BP measurement in upright position, particularly
in diabetic patients !)
• do not attempt aggressive lowering
of systolic blood pressure,
if diastolic blood pressure is very low
Asymptomatic or symptomatic coronary artery disease
in CKD or ESRD
To treat or not to treat ?
Observational studies
640 Endstage renal disease patients
Acute myocardial infarction
One year survival:
- medical therapy 45 %
- percutaneous coronary intervention (PCI) 54 %
-coronary artery bypass grafting (CABG) 69 %
Chertow, AJKD (2000) 35:1044
Prospective data collection non-dialysis dependent kidney disease
and in dialysis dependent CKD
CABG –
survival advantage for all categories of kidney function
PCI –
lower risk of death in dialysis and reference patients compared with no revascularisation
Hemmelgarn, Circulation (2004) 110:1890
Yasuda, JASN (2005) 17:2322
study in hemodialysis patients (n=259)
coronary angiography (137 had lesions),
optional PCI (decided by patient),
all cause and cardiac 5-year survival higher in PCI group
Yasuda, JASN (2005) 17:2322
ENDSTAGE KIDNEY
DISEASE
CARDIOVASCULAR
EVENTS
if 70%-90% kidney function lost
results of treatment poor
de Jong, CJASN (2008) 3:616
Survival on hemodialysisCV events the major cause of death on dialysis
survival on hemodialysis is like adding 50 years to the patient‘s life
Eknoyan, MEM(1999) 25:100
the life expectancy of the 30 year old grandson on dialyisis is the same
as that of his 85 year old grandmother
100
GP Male
Annual Mortality (%)
10
GP Female
GP Black
1
GP White
Dialysis Male
0.1
Dialysis Female
Dialysis Black
0.01
Dialysis White
0.001
25-34
35-44
45-54
55-64
65-74
75-84
> 85
Age (years)
Sarnak . Am J Kidney Dis. 2000;35(suppl1):S117
Stunning –
ischemia induced global or regional LV wall
contraction abnormalities and impaired systolic LV function
Progressive reduction
of shortening fraction in
LV segments with
regional motion abnormalities
(stunning)
Previously stunned
myocardial segments –
reduced ejection fraction at rest
and during dialysis
Burton, CJASN (2009) 4:1925
Overall mortality
Cardiovascular mortality
Correlation between aortic
calcification (AAC)
and
overall as well as
cardiovascular mortality
Okuno, Am.J.Kidn.Dis.(2007) 49:417
Relation between renal function and
presentation, use of therapies and in-hospital complications
in acute coronary syndrome
SWEDEHEART register
Nationwide coronary care unit registry 2003-2006 in Sweden
477 consecutive MI patients with CKD (MDRD)
compared to patients without CKD :
# fewer chest pain (67% vs 90%; p<0.001)
# Killip I (58% vs 89%; p<0.001)
# STEMI (ST-elevation) (22% vs. 41%; p<0.001)
Szummer, J.Intern.Med.(2010) 268:40
In hospital mortality according to eGFR and admission ECG
Szummer, J.Intern.Med.(2010) 268:40
Relation between renal function, presentation and
use of therapies
in acute coronary syndrome
SWEDEHEART register
Nationwide coronary care unit registry 2003-2006 in Sweden
477 consecutive MI patients with CKD (MDRD)
lower renal function:
in non-ST elevation MI less frequent use of anticoagulant and revascularisation
in STEMI :
less frequent use of anticoagulant and revascularisation
with moderate, but decreased in severe renal dysfunction
Reperfusion shifted from PCI to fibrinolysis
Szummer, J.Intern.Med.(2010) 268:40
Cardiac sequelae of primary kidney disease
e.g. glomerulonephritis, polycystic kidney disease…
• ventricular hypertrophy (lv + rv)
• cardiac interstitial fibrosis
• microvascular disease
(postcoronary arterioles, capillaries)
Cardiomyocyte hypertrophy and
myocardial interstitial fibrosis in uremia –
implications for cardiac compliance
Mall, Kidn.Internat.(1988) 33:804
normal morphology
morphology of the myocardium of a patient
with chronic renal failure
Intramyocardial postcoronary arteries
in renal failure
uremia
control
afterload
(resistance, impedance)
myocyte thickening
concentric hypertrophy
preload
(hypervolemia, anemia)
myocyte lengthening
excentric hypertrophy
ventricular LV (+RV?)
hypertrophy
amplifying factors :
(uremia- specific?
BP/ volemia independent)
neurohumoral activation
(sympathetic overactivity)
active vitamin D,PTH,
FGF23 ↑
mTOR
cardiotonic steroids