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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
10
20
30
40
50
60
70
80 Primary outcome
0
10
20
30
40
50
60Myocardial infarction
0
10
20
30
40Cardiovascular death
0
10
20
30
40
50
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
000 p
ers
one/
ann
o
Eve
nti/ 1
000 p
ers
one/
ann
o Eve
nti/ 1
000 p
ers
one/
ann
o
Eve
nti/ 1
000 p
ers
one/
ann
o
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
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4
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