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Lettura:Nell’interpretazione della sindrome cardio-renale: quale è il ruolo della funzione renale dal punto di vista del cardiologo?
Prof. Livio Dei CasCattedra e U.O. di CardiologiaDipartimento di Medicina Sperimentale ed ApplicataDipartimento Cardio-toracicoUniversità e Spedali Civili di Brescia
9th International Symposium Heart Failure & Co. Milano, Istituto Clinico Humanitas
Decreased cardiacperformance
Decreased cardiac output /
increased venous pressure
Impaired renal function
↓renal perfusion, ↑ renal venous pressure
Increased waterand Na+ retention
The Cardio-renal syndrome
Hypertension
Neurohormonal activation, inflammation,
oxidative stress Neurohormonal activation,
inflammation, oxidative stress
L Dei Cas, 1989
Cardio-renal syndrome: a definition
• Presence or development of renal dysfunction in patients with cardiac dysfunction
– Chronic heart failure
– Acute heart failure
• Patients are volume overloaded and/or with low cardiac output (dehydration must be excluded)
Cardio-renal syndrome
• Epidemiology
• Prognostic significance
• Mechanisms of renal damage
• Treatment
Cardio-renal syndrome
• Epidemiology
• Prognostic significance
• Mechanisms of renal damage
• Treatment
GFR, ml/min/1.73 m2 GFR, ml/min/1.73 m2
33% of patients with eCrCl <60
ml/min
60% of patients with eCrCl <60
ml/min
Prevalence of cardio-renal syndrome
Anavekar et al., New J Med 2004; 351:1285 Heywood et al., J Card Fail 2007; 13:422
Gottlieb et al., J CardFail 2002; 8:136
Prevalence of worsening function in acute heart failure
Cardio-renal syndrome
• Epidemiology
• Prognostic significance
• Mechanisms of renal damage
• Treatment
Prognostic significance of cardio-renal Prognostic significance of cardio-renal syndromesyndrome
• Patient at risk of cardiovascular events Patient at risk of cardiovascular events
• Chronic heart failureChronic heart failure
• Acute heart failureAcute heart failure
Prognostic significance of cardio-renal Prognostic significance of cardio-renal syndromesyndrome
• Patient at risk of cardiovascular events Patient at risk of cardiovascular events
• Chronic heart failureChronic heart failure
• Acute heart failureAcute heart failure
Renal insufficiency as a predictor of cv outcomes and the impact of ramipril: the
HOPE randomized trial
Mann et al., Ann Intern Med 2001; 134:629
Renal insufficiency as a predictor of cv outcomes and the impact of ramipril: the
HOPE randomized trial
Mann et al., Ann Intern Med 2001; 134:629
Anavekar, N. S. et al. N Engl J Med 2004;351:1285-1295
Relation between Glomerular Filtration Rate and Outcome after Myocardial Infarction with LV Dysfunction and/or CHF and Serum Creatinine <2.5 mg/dl: VALIANT Trial
All Cause Mortality CV Composite End Point
Hazard Ratio for Death From Any Hazard Ratio for Death From Any Cause, According to eGFR at BaselineCause, According to eGFR at Baseline
1414
1212
1010
88
66
44
22
0000 2020 4040 80806060 100100 120120 140140
Estimated GFR (mL/min/1.73 mEstimated GFR (mL/min/1.73 m22))
Haz
ard
rat
io (
95%
CI)
fo
r H
azar
d r
atio
(95
% C
I) f
or
dea
th f
rom
an
y ca
use
dea
th f
rom
an
y ca
use
Anavekar NS, et al. Anavekar NS, et al. N Engl J MedN Engl J Med. 2004;351:1285-1295.. 2004;351:1285-1295.
Prognostic significance of cardio-renal Prognostic significance of cardio-renal syndromesyndrome
• Patient at risk of cardiovascular events Patient at risk of cardiovascular events
• Chronic heart failureChronic heart failure
• Acute heart failureAcute heart failure
81%
72% 70%
86%
Serum creatinine
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30 36
Months
Fra
ctio
n o
f pat
ien
ts
Glomerular filtration rate
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30 36
Months
Creatinine > 1.2 mg% (n=96)
Creatinine < 1.2 mg% (n=99)
P = 0.07
GFR > 70 ml/hr (n=100)
GFR < 70 ml/hr (n=95)
P = 0.003
Freedom from Death of the Patients Assessed Before Beta-blocker Treatment. Value of Renal Function
Dei Cas et al., 2006
Proportional Relationship of eGFR With Proportional Relationship of eGFR With Mortality in Cox-Adjusted Survival Mortality in Cox-Adjusted Survival
Analysis: data from PRIME IIAnalysis: data from PRIME II
0.00.0GFRc (mL/min)GFRc (mL/min) > 76> 76 59 – 7659 – 76 44 – 5844 – 58 < 44< 44LVEF (%)LVEF (%) > 30> 30 26 – 3026 – 30 20 – 2520 – 25 < 20< 20
0.50.5
1.01.0
1.51.5
2.02.0
2.52.5
3.03.0
3.53.5
4.04.0 1.01.0
0.90.9
0.80.8
0.70.7
0.60.6
0.50.5
0.40.4
0.30.300 250250 500500 750750 1,0001,000 1,2501,250
DaysDays
> 76 mL/min> 76 mL/min
59 – 76 mL/min59 – 76 mL/min
44 – 58 mL/min44 – 58 mL/min
< 44 mL/min< 44 mL/minRel
ativ
e ri
sk f
or
mo
rtal
ity
Rel
ativ
e ri
sk f
or
mo
rtal
ity
Pro
po
rtio
n s
urv
ival
Pro
po
rtio
n s
urv
ival
GFRcGFRc
LVEFLVEF
Hillege HL, et al. Circulation. 2000;102:203-210. Hillege HL, et al. Circulation. 2000;102:203-210.
Survival by Baseline GFR in SOLVD Survival by Baseline GFR in SOLVD (6630 patients)(6630 patients)
Al-Ahmad et al., JACC 2001; 38:955
Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart
Failure. Results from CHARMCHARM
Low LVEF Low LVEF Preserved LVEFPreserved LVEF
Hillege et al., Circulation. 2006;113:671-678
Prognostic significance of cardio-renal Prognostic significance of cardio-renal syndromesyndrome
• Patient at risk of cardiovascular events Patient at risk of cardiovascular events
• Chronic heart failureChronic heart failure
• Acute heart failureAcute heart failure
Serum Creatinine at Discharge and Outcome in patients discharged after an AHF Hospitalization
P=0.008P=0.040
S-Creatinine ≤ 1.3 mg/dl
S-Creatinine >1.3 mg/dl S-Creatinine ≤ 1.3 mg/dlS-Creatinine >1.3 mg/dl
Dei Cas et al. in press
Variables Selected by Multivariable Analysis for the Prediction of Mortality
HFSS EFFECT ADHERE OPTIME-CHF
Age v v v
Heart rate v v
SBP v v v v
Resp. Rate v
LBBB v
LVEF v
pVO2 v
BUN v v v
s-Sodium v v v
CAD v
Comorbidities v
NYHA class v
ADHERE: Risk Stratification for Inhospital ADHERE: Risk Stratification for Inhospital Mortality in the Validation CohortMortality in the Validation Cohort
32,229 hospitalizations
BUN < 43 mg/dLMortality, 2.8%
BUN ≥ 43 mg/dLMortality, 8.3%
24,702 hospitalizations 6,697 hospitalizations
SBP ≥ 115 mmHg
Low risk2.3% mortality
SBP< 115 mmHg
Intermediate risk5.7% mortality
SBP ≥ 115 mmHg
Intermediate risk5.6% mortality
SBP< 115 mmHg
15.3% mortality
1,862 hospitalizations
S-creatinine< 2.75 mg/dL
Intermediate risk13.2% mortality
S-creatinine≥ 2.75 mg/dL
High risk19.8% mortality
Fonarow GC, et al. JAMA. 2005;293:572-580.Fonarow GC, et al. JAMA. 2005;293:572-580.
Patients at risk Patients at riskAbsolute and percent s-Cr change: Absolute s-Cr change:
< 0.3 or 25% 211 143 92 55 36 < 0.3 184 125 79 46 33 ≥ 0.3 & 25% 107 64 36 19 14 ≥ 0.3 134 82 49 27 21
HF hospitalizations andCV-mortality–free survival
55%
28%
0.0
0.2
0.4
0.6
0.8
1.0
0 90 180 270 360 450 540 630 720
Days
Pat
ien
ts (
%)
CV-mortality–free survival
P < 0.001
Δ creatinine < 25% and/or < 0.3 mg/dLΔ creatinine ≥ 25% and ≥ 0.3 mg/dL
86%
59%
0.0
0.2
0.4
0.6
0.8
1.0
0 90 180 270 360 450 540 630 720Days
Prognostic Significance of Worsening Prognostic Significance of Worsening Renal Function in Patients With ADHFRenal Function in Patients With ADHF
P < 0.001
Δ creatinine < 25% and/or < 0.3 mg/dLΔ creatinine ≥ 25% and ≥ 0.3 mg/dL
Pat
ien
ts (
%)
Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.
Worsening Renal Function and outcome
lower risk for WRF higher risk for WRF
.1 .2 .5 1 2 4 8
Study Odds ratio (95% CI) Inhospital patients Krumholz (2000), n=1681 1.41 ( 1.10, 1.82) Smith (2003), n=412 1.73 ( 1.00, 2.98) Akhter (2004), n=480 2.62 ( 1.66, 4.13) Cowie (2006), n=299
Jose (2006), n=1854 Khan (2006), n=6535
Owan (2006), n=6052
Outhospital patients
Subtotal
De Silva (2005), n=1216
Subtotal
Overall
1.44 ( 0.98, 2.09)
1.61 ( 1.35, 1.93)
1.71 ( 0.96, 3.05)
1.46 ( 1.06, 2.02)
1.49 ( 1.30, 1.71)
1.69 ( 1.48, 1.94) 1.79 ( 1.59, 2.02)
1.62 ( 1.45, 1.82)
Damman et al. J Card Fail 2007
Why is renal dysfunction an independent prognostic factor in heart failure
• Need of higher diuretics doses
• Lower tolerance of life saving therapies (RAA inhibitors)
• Anemia
• Neurohormonal & inflammatory activation
• Oxidative stress, endothelial dysfunction
• ???...
Ahmed, A. et al. Eur Heart J 2006 27:1431-1439
Chronic diuretic use and increase in mortality: a retrospective analysis with propensity score methods
from DIG trial
All cause mortality Heart failure mortality
Predictors of Worsening Renal Failure Among 318 Patients Hospitalized for AHF
Results of Multivariable Analysis
PredictorPredictor Odds ratio (95% CI)Odds ratio (95% CI) PP
History of chronic kidney diseaseHistory of chronic kidney disease 1.84 (1.04 – 3.27)1.84 (1.04 – 3.27) < 0.0001< 0.0001
IV furosemide dose > 100 mg/d IV furosemide dose > 100 mg/d 2.18 (1.27 – 3.73)2.18 (1.27 – 3.73) 0.0040.004
NYHA class (IV vs. III)NYHA class (IV vs. III) 2.07 (1.24 – 3.45)2.07 (1.24 – 3.45) 0.0050.005
LV ejection fraction < 30%LV ejection fraction < 30% 1.66 (1.01 – 2.75)1.66 (1.01 – 2.75) 0.0470.047
Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.
Kittleson, M. et al. J Am Coll Cardiol 2003;41:2029-2035
Prognostic significance of intolerance to ACE inhibitors for Circulatory-Renal limitations
(CRLimit)
On ACEi, n=173
CR Limit, no inotropes, n=45
1.0 –
0.9 –
0.8 –
0.7 –
0.6 –
0.5 –
0.4 –
0.3 –
0.2 –
0.1 –
0.0 –I I I I I I I I I I I I I I 0 2 4 6 8 10 12 14 16 18 20 22 24 26
149120
9066
46 3231
1030
22
1612 7 5 3 1
CRLimit vs. on ACE: HR, 2.8 (1.8 to 4.4; p<0.0001) adjusted for age, SBP, creatinine…
Months from hospitalization
Eve
nt-
free
su
rviv
al
CR Limit, on inotropes, n=14
3
Inotropes vs. no inotropes: p=0.0002
Impact of congestive heart failure, chronic kidney disease, and anemia on survival in the Medicare
population. An analysis of 1,136,201 patients
Herzog et al. J Cardiac Fail 2004
Cardio-renal syndrome
• Epidemiology
• Prognostic significance
• Mechanisms of renal damage
• Treatment
Damman, K. et al. J Am Coll Cardiol 2009;53:582-588
Increased Central Venous Pressure Is Associated With Impaired Renal Function in Patients With CV Disease:
Curvilinear Relationship Between CVP and eGFR According to Different Cardiac Index Values
P=0.0217Solid line = cardiac index <2.5 l/min/m2; dashed line = cardiac index 2.5 to 3.2 l/min/m2; dotted line = cardiac index >3.2 l/min/m2.
Central venous pressure
Determinants of Glomerular filtration rate in patients with heart failure
Variable Univariate analysis Partial R P value
Multivariate analysis Partial R P value
Age -0.338 0.001
Gender -0.312 0.003
Renal blood flow 0.888 <0.001 0.938 <0.001
Filtration fraction 0.573 <0.001 0.786 <0.001
Urinary albumin excretion -0.306 0.005
Mean BP 0.306 0.005
Hemoglobin 0.312 0.004 -0.520 <0.001
NT-proBNP -0.533 <0.001
Plasma renin activity -0.501 <0.001
sVCAM-1 -0.279 0.010
Nox -0.276 0.011
ADMA -0.168 0.126
CRP -0.016 0.88
Damman et al. Clin Res Cardiol 2009; 98:121
Regulation of Intraglomerular Pressure
Role of Angiotensin II in the Pathogenesis of Renal Disease
Ang II
Efferentconstriction
PG, NOAfferentdilation
Glomerular hypertension
Proteinuria
Focal segmental glomerulosclerosis
Hypertension
TGF-
Extracellular matrixInterstitial fibrosis
PG = prostaglandin; NO = nitric oxide.
High Prevalence of Microalbuminuria in Chronic Heart Failure Patients
Van de Wall et al., J Card Fail 2005; 11:602
Neurohormonal markers in patients with heart failure with and without
microalbuminuria
Van de Wall et al., J Card Fail 2005; 11:602
Relation between Renal Blood Flow and Urinary Albumin Excretion in patients with
Heart Failure
Damman et al. Clin Res Cardiol 2009; 98:121
Cardio-renal interactions in heart failure
Heart failure
↓renal blood flow
↓Glomerular filtration rate
↑diuretics
Salt water retention
↑venous congestion
Worsening renal function
anemia
Albuminuria
Treatment and cardio-renal syndrome
Inotropic agents
Vasodilators
Vasopressin antagonists
Adenosine antagonists
Ultrafiltration
RAA inhibitors
Holmes CL, et al. Holmes CL, et al. ChestChest. 2003;123:1266-1275.. 2003;123:1266-1275.
A Meta-Analysis of the Use of A Meta-Analysis of the Use of Dopamine in Acute Renal FailureDopamine in Acute Renal Failure
Levosimendan Improves Renal Function in Levosimendan Improves Renal Function in Patients With ACHF Awaiting HTxPatients With ACHF Awaiting HTx
1.92 1.92 1.60 1.60
Zemljic G, et al. Zemljic G, et al. J Card Fail.J Card Fail. 2007;13:417-421. 2007;13:417-421.
2.42.4
2.22.2
2.02.0
1.81.8
1.61.6
1.41.4
1.21.2
1.01.0BaselineBaseline 3 months3 months
Cre
atin
ine
(mg
/dL
)C
reat
inin
e (m
g/d
L)
LevosimendanLevosimendan
1.91 1.91 1.90 1.90
2.42.4
2.22.2
2.02.0
1.81.8
1.61.6
1.41.4
1.21.2
1.01.0BaselineBaseline 3 months3 months
Cre
atin
ine
(mg
/dL
)C
reat
inin
e (m
g/d
L)
ControlsControls
Risk of Worsening Renal Function with Nesiritide in Patients with ADHF
A, nesiritide <0.03 μg/kg/min vs non-inotrope based controls; B, nesiritide <0.03 μg/kg/min vs all controls; nesiritide <0.015 μg/kg/min vs non-inotrope based controls; C,nesiritide <0.015 μg/kg/min vs non-inotrope based controls; D, nesiritide <0.015 μg/kg/min vs all controls; E, nesiritide <0.06 μg/kg/min vs non-inotrope based controls; F, nesiritide <0.06 μg/kg/min vs all controls
0 0.5 1 1.5 2 2.5
F
E
D
C
B
A
Risk ratio (95% CI)
Nesiritide better Nesiritide worse
Sackner-Bernstein et al., Circulation 2005; 111:1487
OutpatientInpatient
EVEREST: Changes in Renal Function EVEREST: Changes in Renal Function with Tolvaptanwith Tolvaptan
BUN (mg/dL)
Serum Cr (mg/dL)
-0.4
-0.2
0.0
0.2
0.4
0.6
Day1
Day 7 orDischarge
1 4 8 16 24 32 40 48 56
19121925
18641886
17551761
16201614
13811382
11681203
955978
813821
675677
525537
TLVPLC
-4
-2
0
2
4
6
8
Day1
Day 7 orDischarge
1 4 8 16 24 32 40 48 56
TLVPLC
19801987
18281820
16871674
14331434
12201247
10011014
851853
713706
558559
19401951
TolvaptanPlacebo
After Discharge (wk)Inpatient
EVEREST: Tolvaptan in ADHFEVEREST: Tolvaptan in ADHF
1.01.0
0.90.9
0.80.8
0.70.7
0.60.6
0.50.5
0.40.4
0.30.3
0.20.2
0.10.1
0.00.02424212118181515121299663300
Months in studyMonths in study
Pro
po
rtio
n s
urv
ivin
gP
rop
ort
ion
su
rviv
ing
All-cause mortalityAll-cause mortality
Log-rank test: Log-rank test: PP = 0.76 = 0.76PetoPeto––PetoPeto––Wilcoxon Test: Wilcoxon Test: PP = 0.68 = 0.68Stratified PetoStratified Peto––PetoPeto––Wilcoxon Test: Wilcoxon Test: PP = 0.68 = 0.68
Est. 1-year Est. 1-year mortalitymortality, 25 vs. 26%; HR 0.98, 25 vs. 26%; HR 0.98
TolvaptanTolvaptanPlaceboPlacebo
Konstam MA, et al. Konstam MA, et al. JAMAJAMA. 2007;297:1319-1331.. 2007;297:1319-1331.
Elkayam, U. et al. J Am Coll Cardiol 1998;32:211-215
Effects of adenosine on renal haemodynamics
Renal blood flowRenal blood flow Renal vascular resistanceRenal vascular resistance
Change in Urine Volume andrenal function with Furosemide and Adenosine
antagonist (BG9719)
00 500500 10001000 15001500 20002000 25002500
Urine outputUrine output0 – 8 hours0 – 8 hours (mL) (mL)Day 1 – BaselineDay 1 – Baseline
ΔΔ G
FR
GF
R1
– 8
ho
urs
1
– 8
ho
urs
(%)
(%)
Placebo
Furosemidealone
BG9719 +Furosemide
BG9719
Gottlieb SS, et al. Gottlieb SS, et al. CirculationCirculation. 2002;105:1348-1353.. 2002;105:1348-1353.
−25
−20
−15
−10
−5
0
5
10
15
20
PROTECT Pilot Change in Serum Creatinine
−0.05
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
Day 2 Day 3 Day 7 Day 14Mea
n c
han
ge
in s
eru
m c
reat
inin
e (m
g/d
L)
Placebo (n = 78)10 mg (n = 74)20 mg (n = 75)30 mg (n = 74)
*Nominal P < 0.05 for dose-related trend at Day 14
Cotter G, et al. J Card Fail. 2008;14:631-640.Cotter G, et al. J Card Fail. 2008;14:631-640.
Ultrafiltration in Advanced HF
Clinical benefits: ↓ peripheral and pulmonary
edema ↓ PA pressures ↓ neurohormonal activation ↑ subsequent diuretic efficacy
Persistent effects for several months
Freedom From Heart Failure Rehospitalization in UNLOAD
100100
8080
6060
4040
2020
0000 1010 2020 3030 4040 5050 6060 7070 8080 9090
Ultrafiltration arm (16 events)Ultrafiltration arm (16 events)
Standard care arm (28 events)Standard care arm (28 events)
PP = 0.037 = 0.037
Number of patients at riskNumber of patients at riskUltrafiltration Ultrafiltration 8888 8585 8080 7777 7575 7272 7070 6666 6464 4545Standard care Standard care 8686 8383 7777 7474 6666 6363 5959 5858 5252 4141
Pat
ien
ts f
ree
fro
mP
atie
nts
fre
e fr
om
reh
osp
ital
izat
ion
(%
)re
ho
spit
aliz
atio
n (
%)
DaysDays
Costanzo MR, et al. Costanzo MR, et al. J Am Coll CardiolJ Am Coll Cardiol. 2007;49:675-683.. 2007;49:675-683.