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.