Understanding the Cardio-Renal Syndromes

Alberto Palazzuoli

Department of Internal Medicine Cardiology Unit S. Maria alle Scotte Hospital, University of Siena Italy

The Cardio-Renal axis: an underestimated player in cardiovascular diseases ESC Congress Munich 27/08/2012

Regulation of volume and BP (Na+ and H2O)

Electrolyte and acid-base balance

Hormonal function (Erythropoiesis – Vascular tone)

Blood purification from metabolic waste products

Regulation of perfusion pressure and flow to periphery

Electrical activity depend on electrolytes and acid-base

Contractility depend on O2, volume, electrolytes, toxin

Hormonal function (ANP - BNP)

ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

Heart and Kidney: Dangerous liaison

The Cardio-Renal Syndrome (CRS)

• How can we define it?

• Is an early diagnosis of AKI important?

• What is the exact significance of WRF?

• What is the link between heart and kidney?

• What is the prevalent pathophysiological mechanism??

ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

Common Characteristics of the Cardiorenal Syndrome

Palazzuoli, Ronco Heart Fail Rev 2011

Reduced renal blood

flow and GFR

Increased vascular

resistance

Increased venous

congestion

RAAS activity

Tubular and

glomerular damage

Diuretic resistance

Inflammatory

activation, endothelial dysfunction

Albuminuria

Increased BUN

Anemia

Heart

Kidney Fluid overload

Cardio Renal Syndromes

acute

chronic

Cardio-Renal Reno-Cardiac

Secondary Cardio-Renal

Ronco, C. et al. J Am Coll Cardiol 2008

The cardiorenal syndrome in heart failure

Damman K et al. Prog Cardiovas Dis. 2011

When the Creatinine Rises…

• Patient can’t go home

• Diuretic doses are often decreased

• RAAS inhibitors are often discontinued

• Other medications are renally dosed

• Inotropes may be initiated

• PA catheter may be placed

• Foley catheter may be placed

• Renal advise may be ordered (and is rarely helpful)

0

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80 Primary outcome

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60Myocardial infarction

0

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40Cardiovascular death

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60 All death

All patients Placebo Ramipril

Primary Outcome Myocardial Infarct Cardiovascular Death in pz. with creatinine <1.4 mg/dl or 1.4 mg/dl

Creatinine < 1.4 mg/dl

Creatinine <1.4 mg/dl

Creatinine

<1.4 mg/dl Creatinine <1.4 mg/dl

Creatinine 1.4 mg/dl

Creatinine 1.4 mg/dl

Creatinine 1.4 mg/dl

Creatinine 1.4 mg/dl

HOPE Trial, Ann Intern Med, 2001

Eve

nti/ 1

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Kidney Function Stage

Parameter I (n=10,660)

II (n=32,433)

III (n=51,533)

IV (n=15,553)

V (n=82769) p†

Age, mesn (SD), y 61.7 815.9) 70.1 (14.7) 75.7 (12.0) 76.3 (11.6) 67.4 (14.7) <.0001

Atrial fibrillation 19.3 28.6 35.0 34.7 19.8 <.0001

Diabetes 38.0 37.4 45.0 53.6 55.1 <.0001

Hypertension 68.2 70.3 73.0 76.7 85.0 <.0001

Peripheral vascular disease 10.7 13.6 19.1 24.3 24.7 <.0001

Renal insufficiency 2.9 5.8 28.7 70.9 94.6 <.0001

BNP, pg/mL, n 3845 13,243 22,449 6800 2623 ns

Hb, means (SD), g/dL 13.0 (2.6) 13.0 (2.5) 12.3 (2.5) 11.4 (2.3) 11.5 (2.5) <.0001

† Accross stage using chi-square tests for categoric variables and analysis of variance for continuos variables

Heywood JT et al, J Card Fail, 2007

Demographic and Baseline Characteristics by Kidney Function Stage in ADHERE Database

Quartile 1

(n=234)

Quartile 2

(n=235)

Quartile 3

(n=234)

Quartile 4

(n=234)

P

eGFR, mL•min -1·1.73 m-2 82 (75-94) 60 (55-65) 45 (42-48) 29 (25-33) <0.01‡

Primary end point, d 5 (4-10) 6 (4-13) 7 (4-14) 8 (5-17) <0.01

Deaths, n(%)

In hospital * 1 (0.44) 3 (1.3) 8(3.4) 16 (6.8) <0.01

At 60 days † 10 (4.3) 9 (3.9) 25 (10.8) 44 (19) <0.01

Hazards ratio (95% CI) Referent 0.9 (0.37-2.22) 2.63 (1.26-5.48) 4.73 (2.38-9.39)

Readmissions/death within 60 days, n (%) † 53 (22.9) 71 (31) 93 (40.1) 106 (45.3) <0.01

Odds ratio (95% CI) Referent 1.51 (1-2.29) 2.25 (1.5-3.37) 2.8 (1.86-4.15)

Main Clinical Outcomes by eGFR Quartiles: OPTIME-HF

*Odds ratios for in-hospital death are questionable because of the small numbers of events and thus are not presented

†Raw percentages of patients followed up to the 60-day visit. Cox proportional-hazards regression using indicator variables was used to analyze 60-

day death rate. Categorical variables were analyzed with logistic regression. Probability values represent overall relationship with eGFR as a

continuous variable for regression models.

‡All individual quartiles vs lowest quartile, p<0.05

Klein M et al, Circ Heart Fail, 2008

Nohria et al ESCAPE Trial JACC 2008

Relationship Between Renal Parameters and 6-Months Outcomes

Time to Death Time to Death or Rehospitalization

HR* 95% CI P Value HR* 95% CI p Value

Baseline SCr 1.20 1.11–1.29 < 0.0001 1.14 1.08–1.21 <0.0001

Baseline eGFR 1.25 1.13–1.38 <0.0001 1.10 1.05–1.15 <0.0001

Discharge SCr 1.30 1.20–1.41 <0.0001 1.14 1.08–1.21 <0.0001

Discharge eGFR 1.28 1.14–1.43 <0.0001 1.09 1.03–1.15 0.002

> 0.3 mg/dl ↑ SCr† 1.31 0.81–2.10 0.27 1.26 0.96–1.64 0.09

> 25% 2 eGFR‡ 1.49 0.91–2.44 0.12 1.06 0.79–1.43 0.69

*Hazard ratio (HR) calculated per 0.3-mg/dl increments in serum creatinine (SCr) and per 10-ml/min decrements in estimated

glomerular filtration rate (eGFR). Worsening renal function, defined as:

1) †an increase in SCr 0.3 mg/dl; and 2) ‡a decrease in eGFR 25% from baseline to discharge, is treated as a dichotomous variable.

CI confidence interval.

Tokmakova et al SAVE Study Circulation 2008

Kaplan-Meier curves for CV mortality/morbidity stratified by eGFR: SAVE study

60%

50%

40%

30%

20%

10%

0%

1 year 2 year 3 year 4 year

eGFR <60, placebo

eGFR <60, captopril

eGFR >60, placebo

eGFR >60, captopril

Years post-MI

% E

ven

ts

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0.5

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0 1 2 3 4

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Kaplan-Meier plot of cumulative incidence of cardiovascular death or unplanned admission to hospital for the management of worsening CHF in patients with

reduced LVEF and preserved LV systolic function

<45.0

45.0 – 60.0

> 60.0

<45.0

45.0 – 60.0

> 60.0

years

years

cu

mu

lativ

e in

cid

en

ce

c

um

ula

tiv

e in

cid

en

ce

Hillege et al CHARM Circulation 2006

38

51

24

0

10

20

30

40

50

60

Any impairment Moderate/severe

impairment

No impairment

%

Smith GL et al, J Am Coll Cardiol 2006

Mortality:

15% for every 0.5 mg/dl increase in creatinine

7% for every 10 ml/min decrease in eGFR

What is the “real” Risk when IR is associated to CHF

HR 1.56 (p= 0.001)

HR 2.31 (p= 0.001)

WRF outcome during hispitalization and at early and post discharge:

COACH study

1.0

0.9

0.6

0.7

0.8

0.0 0 180 120 60 300 240 420 480 540 360

Follow-up time (days)

Cu

mu

lati

ve

su

rviv

al

(de

ath

or

HF

ad

mis

sio

n) WRF in-hospital WRF 0-6 months WRF 6-12 months

Damman K et al. Eur J Heart Fail 2009

No WRF

WRF

Clinical Characteristics and Outcomes of Patients With Improvement in Renal Function During the Treatment of

Decompensated Heart Failure

Testani JM et al. Journal of Cardiac Fail 2011

Potential mechanisms of increased mortality in WRF

Marker of more decompensated HF

Greater prevalence of coexistent diseases

Discontinuation of common treatments

Relationship due to cardio-renal interaction

The “traditional” concept of WRF in acute HF

Decrease in cardiac output

Arterial underfilling

Decreased perfusion pressure

Increased neuro-hormonal

activity

Systemic and Renal

vasocostriction

Glomerular and interstitial

damage

Acute CRS Type 1

Renal hypoperfusion

Reduced oxygen delivery

Necrosis / apoptosis

Decreased GFR

Resistance to ANP/BNP

BIOMARKERS

KIM-1

Cystatin-C

N-GAL

Creatinine

Hemodynamically mediated damage

Immune mediated damage

Humorally mediated damage

Humoral signalling

Cytokine secretion

Exogenous factors Contrast media ACE inhibitors

Diuretics

Acute Kidney Injury

Caspase activation Apoptosis

Caspase activation Apoptosis

Decreased perfusion

Acute decompensation

Ischemic insult

Coronary angiography

Cardiac surgery

Decreased CO Increased venous

pressure

Toxicity Vascocostriction.

RAA activation, Na + H2O retention, vasoconstriction

BNP

Sympathetic Activation

Hormonal factors

Monocyte Activation Endothelial

activation

Natriuresis

Acute Heart Disease

or Procedures

ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

Characteristics overall cohort no SBP-reduction yes SBP-reduction P

Demographics Age (years) 56.4±13.9 57.1±13.3 55.7±14.5 0.309 Males 74,1% 74,1% 74,1% Functional status/ ejection fraction NYHA class (mean class) 3.9±0.4 3.9±0.3 3.9±0.4 0.773

Six minut walk (feet) 422±420 460±445 384±392 0.092 MVO2 (mL/kg/min) 10.1±3.5 10.4±3.9 9.7±2.8 0.324 Ejection fraction 19.5±6.5 19.6±6.7 19.3±6.4 0.684 Systolic blood pressure 101.5±14.7 107.6±15.0 95.5±11.7 <0.001* Admission to discharge change in blood pressure

Absolute 4.3±16.8 8.6±10.0 -17.2±11.5 <0.001* Relative 2.8±15.3 9.1±10.8 -14.7±8.2 <0.001* Laboratory findings

GFR(mL/min/1.73 m2) 56.9±25.2 53.7±25.6 60.1±24.5 0.012* *Significant P- value.

Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes

Testani et al. Eur J of Heart Fail 2011

Influence of renal dysfunction phenotype on mortality in the setting of cardiac dysfunction: analysis of three randomized controlled trials

Testani JM et al. Eur J Heart Fail 2011

* LBC Low BUN creatinine HBC High BUN creatinine

Blood urea nitrogen as biomarker of neurohormonal activation

Kazory A Am J Cardiol 2010

Relationship Between Neurohormones and LVEF and GFRc GFRc LVEF Univariate r Multivariate Univariate Multivariate Norepinephrine −0.28 <0.001 0.001 −0.15 0.004 NS Epinephrine −0.05 0.036 NS −0.15 0.004 0.007 Dopamine −0.23 <0.001 0.001 −0.08 0.143 NS Renin −0.13 0.013 0.005 −0.22 <0.001 NS Aldosterone −0.15 0.005 0.006 −0.04 0.501 NS ANP −0.35 <0.001 <0.001 −0.27 <0.001 0.002 N-terminal ANP −0.53 <0.001 <0.001 −0.33 <0.001 <0.001 Endothelin −0.10 0.069 NS −0.18 0.001 0.046 Epinine −0.07 0.201 NS −0.01 0.899 NS

Hillege HL et al. Circulation 2000

Adaptive response to renal hypoperfusion in HF

Ruggenenti P et al. Eur H J 2011

VENOUS CONGESTION AND WORSENING RENAL FUNCTION

Mullens et al, JACC, 2009

Relation among renal dysfunction and Congestion in CHF

Damman K et al Eur J Heart Fail 2010

Variable Death, Transplant, or HF Rehospitalization Univariable HR (95% CI)* Univariable P Value Multivariable HR (95% CI)*

Multivariable P Value Previous HF 1.73 0.005 1,79 0.01 0.01 CKD 1.69 <0.0021 1.87 0.008

Laboratory characteristics Plasma hemoglobin, 0.59 <0.0035 Serum sodium, admission 0.6 <0.0001 Serum sodium, discharge 0.48 0.001 Congestion and WRF . 1: Yes WRF and yes congestion 5.35 <0.0001 2.44 0.009 1.39 (0.88, 2.2) 0.1597 2: No WRF and yes congestion 1.95 0.136 1.35 0.53 0.2247 3: Yes WRF and no congestion 1.24 0.42 1.04 0.88 Reference: No WRF and no congestion Ref Ref

Metra et al Circ Heart Fail 2012

Is WRF as ominous prognostic sign in AHF patients? The role of congestion

Changes in renal parameters and Intra abdominal pressure

Mullens W et al J Am Coll Cardiol 2008

Changes in IAP and serum creatinine in patients underwent to paracentesis or ultrafiltration

Mullens W et al J Cardiac Fail 2008

Fluid overload re-distribution

Increased vascular

resistance

Increased venous return and preload

Reduced capacitance in

veins

Increased arterial

stiffness leads to hightened

afterload

Cotter G et al Eur J Heart Fail 2008

Fluid overload: redistribution and accumulation mechanisms

Interaction among fluid overload cardiac output and mean blood pressure

Haemodinamic control (Guyton)

Volume expansion

Increased cardiac output

Total body autoregolation

Increased peripheral resistance

Increased blood pressure

Pressure natriuresis

Cardiorenal connection

NO-ROS Dysbalance

Sympathetic Nervous Systolic Activation

Renin Angiotensin System Activation

Inflammation

Cardiovascular damage

Renal

failure

Heart

failure

Bongartz L G et al. Eur Heart J 2005

Peripheral vascular

resistance

Arterial Underfilling

Cardiac output

Renal hemodinamics and renal

salt/water excretion

Pulmonary

hypertension RV failure

Venous congestion

Renal interstitial

pressure

Neurohormonal

Activation

↑ SNS activity

↑ RAAS activity

↑ AVP release

↑ Renal venous

pressure

↑ Intra-abdominal

pressure

? Myocardial

depressant factor

Tang WW et al. Heart 2010

The Perfect Sorm The “Perfect Storm”

Risk

Injury

Failure

Loss

ESRD End Stage Renal Disease

Creatinine Criteria Urine Output Criteria

UO <0.3 mL/kg/h x 24 hr or

anuria x 12 hrs

UO <0.5 mL/kg/h x 12 hr

UO <0.5 mL/kg/h x 6 hr

Creatinine increase x 2

Creatinine increase x 3

or creatinine 4 mg/dL (Acute rise of 0.5 mg/dlL

High Sensitivity

High Specificity

Persistent ARF** = complete loss of renal function > 4 weeks

ADQI ADQI

Increased creatinine x1.5 or Creatinine increase > 0.3

mg/dl

ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

Mortality by RIFLE Class

0

5

10

15

20

25

30

35

40

45

50

Non-AKI Risk Injury Failure

Mo

rtali

ty

13 studies, n >71,000 patients

ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

Acute Reno-Cardiac syndome: epidemiology

Heterogeneity of AKI different methods to define AKI

different risk profile in the enrolled population few studies reporting cardiac events

clinical information about cardiac conditions at baseline

POOR CLINICAL CHARACTERIZATION AND DEFINITION

Cruz D et al Heart Fail Rev 2011

Glomerulonephritis

Preexisting renal insufficiency

Red. extracellular volume

Red. effective arterial volume

Impaired renal microcirculation

Drug toxicity

Rhabdomyolysis

Exogenous toxins

SIRS / sepsis Cardio-Renal

Causes of Acute Kidney Injury

ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

Krämer et al. Am J Med. 1999;106:90.

Neurormonal increase leads to

Diuretic-Resistance

Proximal Tubul Ang II increases Na resorbtion

Glomerul Norepinephrine (and endothelin) reduce blood flow and GRF

Collector Duct Aldosteron increases Na resorbtion

Acute RCS Type 3

Acute Heart

Dysfunction

Glomerular diseases

Interstitial diseases

Acute tubular necrosis

Acute pyelonephritis

Acute urinary obstruction

Acute Kidney Injury

Acute decompensation

Acute heart failure

Ischemic insult

Arrythmias

Decreased CO

BIOMARKERS

Troponin

Myoglobin

MPO

BNP

Humoral Signalling

Cytokine secretion

Hypertension

Caspase activation Apoptosis

Caspase activation Apoptosis Monocyte

Activation

Electrolyte, acid-base & coagulation imbalances

Volume expansion

Decreased GFR

Increased pre-load

Na + H2O retention

Sympathetic Activation

RAA activation,, vasoconstriction

Endothelial activation

ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

Sarnak MJet al, Am J Kidney Dis, 2000

DEGREES OF RENAL AND CARDIOVASCULAR DISEASES

“At risk”

Starting

Progression

End Stage

Renal terminal insufficiency

Insuff. Renal Chronic (FG)

Albuminuria Proteinuria

Age, obesity Diabetes hypertension

Renal Disease Cardiovascular Disease

LV Insufficiency

Cardiovascular Events

Refractory heart failure

Age, obesity Diabetes hypertension

Common factors for heart and kidney diseases

Ronco C et al JACC 2012 (in press)

Parenchimal disease

Artery disease

Congestion and

hypoperfus.

Neuro-endocrine and

cytokine

activation

Treatment for HF

Renal dysfunction

Cleland JG et al Heart Fail Rev 2012

RAAS Effects In Renal and Cardiac diseases

sodium and water reabsrobtion Efferent arterioles constriction proteinuria increase glomerular sclerosis and tubular fibrosis Reduced medullary blood flow blood flow redistribution idrostatic and oncotic pressure

Renal effects

Cardiovascular

effects

vascular muscle cell proliferation and thickness Increase blood pressure Left ventricular hypertrophy and fibrosis Increase atherosclerosis activity neuro hormonal overdrive impairment endothelial function Decrease fibrinolitic acitivity with plateled aggregation

Inflammatory activation: cardiac and renal interaction

Arteries and Veins

Endothelial dysf & vascular stiffness

Kidney

Na retention & fluid intake

Tubulo glomerular damage

Myocardium

Contractility

fibrosis & apoptosis

Inflammation

Congestion Colombo P et al Heart Fail Rev 2012

The role of Inflammation in Cardio-Renal syndrome

Endothelial cells activation

DAMP signaling

Complement activation

Leukocite infiltration

Platelet activation

increase prthrombotic and

Pro coagulative processes

Capillary obstruction

Peristent ischemia

Inflammation

Rosner MH et al. Semin Nephrol 2012

Relationship between CKD and urinary NAG, NGAL and KIM-1.

Damman K et al. Heart 2010

Tubular damage in chronic systolic heart failure is associated with reduced survival independent of

glomerular filtration rate.

Adjusted for age, gender, eGFR, and UACR Multivariable adjusteda

Variable Multivariable HR P-value PCR Multivariable HR P-value PCR

logNAG (per SD) 0.20 0.28

Mortality 1.38 (1.18–

1.61) 0.001 1.30 (1.11–1.51) 0.001

HF hospitalizations

1.22 (1.07–1.40)

0.004 1.17 (1.02–1.33) 0.025

logKIM-1 (per SD)

0.71 0.78

Mortality 1.17 (1.02–

1.34) 0.027 1.14 (0.99–1.31) 0.060

HF hospitalizations

1.13 (1.00–1.28)

0.054 1 11 (0.98–1.26) 0.094

logNGAL (per SD)

0.017 0.023

Mortality 1.24 (1.08–

1.42) 0.021 1 23 (1.07–1.41) 0.003

HF hospitalizations

1.01 (0.90–1.13)

0.90 1 01 (0.90–1.13) 0.85

Clinical outcome of renal tubular damage in CHF

Damman K et al. Eur H J 2011

CONCLUSIONS

• The cardiorenal syndrome is heterogeneous group of pathophysiological entities and the clinical course depends on the prevalent mechanism by which the renal function is impaired

• There is priority to better understand the patophysiologic link between Heart and Kidney, and to know the more sensitive and specific parameters able to identify primitive organ damage their mechanism and significance

• WRF is a mirror of different clinical situation and it should be evaluated taking into account previous cardio-renal damages as well as hemodynamic and non hemodynamic conditions

• Pathophysiologic processes are different in CRS subtypes and involve several actors (hemodynamic, neurohormones, inflammation, fluid overload)

• We need to focus on research agenda designed to recognize the vicious circle of pathological heart-kidney interactions and mechanisms in every clinical condition

• Better assessment of congestion, fluid redistribution, neuro-endocrine overdrive, tubular and glomerular damage, could improve our understanding in CRS