Claudio Ronco, MD Department of Nephrology St. Bortolo Hospital International Renal Research Institute Vicenza - Italy Pathophysiology of Cardio-Renal Interactions 2 nd Human and Veterinary Crosstalk Symposium on Aldosterone For personal use only..® Ceva Santé Animale S.A
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Claudio Ronco, MDDepartment of Nephrology St. Bortolo Hospital
International Renal Research InstituteVicenza - Italy
Pathophysiology of Cardio-Renal Interactions
2nd Human and Veterinary Crosstalk Symposium on AldosteroneFor personal use only..® Ceva Santé Animale S.A
Pathophysiology of Cardio-Renal Interactions
• Heart-Kidney Interactions: Bidirectional Temporally regulated Mediated by different mechanisms Different consequences in specific individuals Functional vs structural damage They may affect other organs
• Cardio Renal Syndrome and its consequences
• The importance of an early diagnosis
Cardio-Renal
Reno-Cardiac
ChronicAcu
te
• Acute Kidney Injuryleading to AHF
• Volume/uremia-induced ADHF• Renal ischemia-induced ADHF• Sepsis/cytokineinduced AKI and HF
• CKD increasing cardiovascular mortality • CKD increasing cardiovascular morbidity • Chronic HF progression due to CKD
• Uremia related HF• Volume related HF
• ADHF leading to AKI• Cardiac Surgery• Cardiac procedures
• CIN• CPB• Valve replacement
• Chronic HF (systolic or diastolic) leading to :
• CKD• CKD progression• Diuretic resistant
oliguria
Cardio-Renal InteractionsBasically a vicious circle
ADHF - CHF
AKI-CKD Physiologicalderangements
Renal dysfunction
Primary Insult
AKI - CKD
ADHF-CHF
Primary Insult
Physiologicalderangements
Heart dysfunction
Heart-Kidney Interactions
Cardiovascular mortality increased by end stage renal dysfunction (ESRD)Cardiovascular risk increased by chronic kidney dysfunction Chronic HF progression due to kidney dysfunction• Uremia related HF• Volume related HF
Acute HF due to acute kidney dysfunction • Volume/uremia-induced AHF
CKD secondary to chronic heart failure (HF)AKI secondary to coronary angiography contrast induced
nephropathy (CIN)AKI secondary to cardiopulmonary bypass (CPB)AKI secondary to acute or acute on chronic heart failure
Pathophysiologic disorder of the heart and kidneys whereby acute or chronicdysfunction in one organ induces acute or chronic dysfunction in the other
CRS Type I (Acute Cardiorenal Syndrome)Abrupt worsening of cardiac function leading to acute kidney injury
CRS Type II (Chronic Cardiorenal Syndrome)Chronic abnormalities in cardiac function causing progressive andpermanent chronic kidney disease
CRS Type III (Acute Renocardiac Syndrome)Abrupt worsening of renal function causing acute cardiac disorders
CRS Type IV (Chronic Renocardiac Syndrome)Chronic kidney disease contributing to decreased cardiac function, cardiachypertrophy and/or increased risk of adverse cardiovascular events
CRS Type V (Secondary Cardiorenal Syndrome)Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac andrenal dysfunction
Markers of FunctionBUN, Creatinine,
GFR/eGFR
AKI CKD
CRS Type 1 CRS Type 2
Markers of DamageNGAL, Cystatin C,
KIM 1
Cardio-Renal Syndrome Type 1
Renal hypoperfusionReduced oxygen deliveryNecrosis / apoptosisDecreased GFRResistance to ANP/BNP
Hemodynamically mediated damage
Immune mediated damage
Neuro-mediated damage
Humoral signalling Cytokine
secretion
Acute Kidney Injury
Caspase activationApoptosis
Caspase activationApoptosis
Decreasedperfusion
Acute decompensationIschemic insultCoronary angiographyCardiac 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
Exogenous FactorsContrast mediaACE inhibitors
Diuretics
Cardio-Renal Syndrome Type 1LCOS and Congestion
Acute Kidney Injury
Acute Heart
Disease
• Upon initial recognition, AKI induced by primary cardiac dysfunctionimplies inadequate renal perfusion until proven otherwise. This shouldprompt clinicians to consider the diagnosis of a low cardiac output state(LCOS) and/or marked increase in venous pressure leading to kidneycongestion.• It is important to remember that central venous pressure translated to therenal veins is a product of right heart function, blood volume, and venouscapacitance which is largely regulated by neuro-hormonal systems.• Specific regulatory and counter-regulatory mechanisms are activated withvariable effects depending on the duration and the intensity of the insult.
Cardio-Renal Syndrome Type 1Hemodynamic mechanisms
Increased preload
Decreased cardiac output
Increased venous
pressure
Diseased heart
Venous congestion
Arterial underfilling
Vasocostriction
Decreased perfusion pressure
Functional(Pre-renal)
Parenchymal
A K I
Vasoconstriction Vasodilatation
Compensatory Mechanisms
Cardio-Renal Syndrome Type 1Compensatory mechanisms in HF
Vasodilatation
HF
Vasocostriction
Compensatory Mechanisms
Sympathetic Nervous System R-A-A System
Arginin Vasopressin Endothelin
Natriuretic Peptides Chinin-kallicrein System
Prostaglandins Endothelial Relaxin Factor
Water excretion
Sodium excretion
Urea readsorption
Water excretion
Sodium excretion
Urea readsorption
Natriuresis
Afterload
Natriuresis
Afterload
ANP - BNP
RAA SYSTEM
SYMPATHETIC NS
VASOPRESSIN
AVP in normal and failing heart
Normal Heart
Failing Heart
INCREASEDATRIAL
PRESSURE
AVP
Sympathetic tone decrease
BNP
Water excretion
Sodium excretion
AVP
Non-osmoticAVP release
V1a-mediatedvasocostriction
BNP
Water excretion
Sodium excretion
RAA
Vasodilat.
Arterial underfilling
Urea readsorption
RAA
V2 receptors
OVERHYDRATION
Time windows for AKI management
Fluids
Drugs
Diuretics
RRT
Nephroprotection?
Length of hospital stay (d)
9060300
Cum
ulat
ive
Surv
ival 1,0
,8
,6
,4
,2
0,0
Non ARD
Risk
Injury
Failure
P<0.001 (Log Rank)
Days after hospital admission
Hoste et al. Crit Care. 2006;10(3):R73
RIFLE max and AKI outcomes
Riskvs NonAKI
Injuryvs NonAKI
Failurevs NonAKI
1 102.4 4.15 6.37Relative Risk
Increase in All-Cause Mortality with worse RIFLE Class
N=71,527 patients
MOLECULAR CELLULAR BIOMARKER CLINICAL
Multiple Timezone Organ Damage Clock Display
Biology of AKI by Time-Zones
BIOMARKERS
C-R
R-C
Chronic Acute
BIOMARKERS
–Sensitive (early appearance) –Easy to detect–Specific (typical of organ injury) –Correlate with severity (prognosis) –Quantitatively describing the level of injury–Capable to indicate treatment initiation and discontinuation–Predicting organ recovery–Predicting progression to CKD
Management of Cardio-Renal Syndromes
Clinical Continuum of AKI
Devarajan, Biomarkers Med 4:265-80, 2010
Structural AKI Biomarkers• Early diagnosis of evolving AKI could result in prevention
and/or earlier changes in management:– Prevention of disease progression either stopping harmful
interventions or mitigating/avoiding exposure to the insult– Early therapeutic interventions designed to protect the kidney
• More accurate differential diagnosis of AKI could direct appropriate therapy of AKI (pre-renal vs renal)
• More accurate staging of AKI could help prognostic stratification and therapy of AKI– Serial staging of phases of AKI (evolution of the syndrome)– Assessment of current and future severity of injury
AKI Biomarkers
McIlroy et al, Anesthesiology 2010; 112: 998-1004
Cardio-Renal Syndrome Type 1
Renal hypoperfusionReduced oxygen deliveryNecrosis / apoptosisDecreased GFRResistance to ANP/BNP
Hemodynamically mediated damage
Immune mediated damage
Humorally mediated damage
Humoral signalling Cytokine
secretion
Acute Kidney Injury
Caspase activationApoptosis
Caspase activationApoptosis
DecreasedperfusionDecreased CO Increased
venous pressure
Toxicity Vascocostriction.
RAA activation, Na + H2O retention, vasoconstriction
BNP
Sympathetic Activation
Hormonal factors
Monocyte Activation Endothelial
activation
Natriuresis
Diuretics & UF
Acute Heart
Disease
Time Course of worsening of renal function (Creatinine increase) in hospitalized HF patients
Gotlieb et Al, JACC 2008
DIURETICS
1.8
1.6
1.4
1.2
0.8
Creatinine
0
500
1000
1500
2000
Day 0 Day 1 Day2 Day 3 Day 4 Day 5
BNP Diuresis
Diuretics
1.8
1.6
1.4
1.2
0.8
Creatinine
0200400600800
100012001400160018002000
Day 0 Day 1 Day2 Day 3 Day 4 Day 5
NGAL BNP Diuresis
NGAL Warning
Stop Diuretics«5B»
Diuretics
Blood Volume
Extracorporeal Uf
Vascular Space
Interstitium Intravascular Refilling
Transcellular water flux
Osmolality
Starling ForcesCardiovascular Conditions
Cardio-Renal Syndrome Type 1
Renal hypoperfusionReduced oxygen deliveryNecrosis / apoptosisDecreased GFRResistance to ANP/BNP
Hemodynamically mediated damage
Immuno mediated damage
Humorally mediated damage
Humoral signalling Cytokine
secretion
Exogenous factorsContrast mediaACE inhibitors
Diuretics
Acute Kidney Injury
Caspase activationApoptosis
Caspase activationApoptosis
DecreasedperfusionDecreased CO Increased
venous pressure
Toxicity Vascocostriction.
RAA activation, Na + H2O retention, vasoconstriction
BNP
Sympathetic Activation
Hormonal factors
Monocyte Activation Endothelial
activation
Natriuresis
INFLAMMATION
Acute Heart
Disease
Current issues in AKI management
APOPTOSIS STUDY IN CRS T.1 and CONTROLS
CTR 72h
11
CRS Type1 72h
78
CTR 96h
11
CRS Type1 96h
81
0
20
40
60
80
100
120
Perc
enta
ge o
f Apo
ptos
is
Evaluation of percentage of apoptosis in U937 cells after incubation with plasma from CRS Type 1 patients and healthy volunteers for 72h and 96h
PlasmaMonocyte
Cell Colture
Apoptosis
Apoptosis
SupernatantR T C
Colture
Cytokines
Cardio-Renal Syndrome Type 1Inflammation/humoral theory
Evaluation of percentage of apoptosis in U937 cells after incubation with plasma from Heart Failure Patients developing CRS Type 1 (HF/AKI) or not (HF/No AKI)
MW CTR 1B 2B 1A 2A
0,0%
20,0%
40,0%
60,0%
80,0%
100,0%
16,5%
28,0%
24h
30,8%
47,6%
48h
36,8%
51,4%
72h
47,0%
58,8%
96h
HF/No AKI
n.6
HF/AKI
n.6
p=0.008 p=0.006 p=0.006 p=0.05
APOPTOSIS STUDY IN HEART FAILURE
Cardio-Renal Syndrome Type 1
Acute Kidney Injury
Acute Heart
Disease
• Occurs in ~25% of unselected patients admitted with ADHF.• Among these patients, pre-morbid CKD is common and predisposes toAKI in approximately 60% of cases.• AKI is an independent risk factor for 1-year mortality in ADHF patientsincluding in patients with ST-elevation myocardial infarction who developsigns and symptoms of heart failure or have a reduced left ventricularejection fraction. This independent effect might be due to an associatedacceleration in cardiovascular pathobiology due to kidney dysfunctionthrough the activation of neurohormonal, cell signaling, oxidative stress,or exuberated repair (fibrosis) pathways.
Cardio-Renal Syndrome: possible pathophysiological mechanisms
of AKI following HF
Gheorghiade M et al. Am J Cardiol. 2005
Hemodynamic deterioration
(congestion, ↓CO, ↓ perfusion)
Myocardial damage injury
Renal dysfunction
(AKI)
Neurohormonal & cytokineactivation
HF progression
Cardiorenal Syndrome Risk Factors
Characteristics Adjusted OR 95% CI P Value
Women 1.41 (1.12-1.77) .003
HTN 1.64 (1.12-2.40) .003
Rales>Bases 1.28 (1.02-1.61) .03
HR >100 bpm 1.34 (1.06-1.68) .01
SCr ≥1.5 mg/dL 1.77 (1.42-2.22) <.001
SBP >200 mm Hg 1.63 (1.13-2.35) .009
Krumholz HM et al. Am J Cardiol. 2000;85:1110.
N=1,681
Obesity and cardiometabolic changes
Obesity
Diabetes
Heart Disease
Kidney Disease
High Blood Pressure
Sleep Apnea
G.I. Tract Disorders
Lean adipose tissue
Obese adipose tissue
TNF-αIL-6
Crosstalk
LeptinResistin
Adiponectin
F F A
Inflammation CRP
Atherosclerosis
Apoptosis
Coronary artery diseaseCardiac
remodellingLVH-Dilatation
Dysmetabolicsyndrome
Chronic ischemia
CKDFibrosis-sclerosis
Présentateur
Commentaires de présentation
It has been shown that the number of adipocytes in the human body can increase tenfold both in number and in size. With such a dramatic increase in fat mass, cytokines and adipokines are produced in large quantities to assure homeostasis of this expanding organ. Many of these cytokines may cause cardiac and renal injury for example IL-6 and TNF-alpha, which are both secreted by adipocytes. Indeed, the production of IL-6 by abdominal adipocytes into the portal circulation to the liver, is the most important stimulus for release of hs-CRP. Thus, hs-CRP are highest in obese individuals and fall to a greater extent with weight loss than any other intervention. Growth of adipocytes and increase in fatty acid content of visceral locations has been consistently demonstrated to be related to obesity generating diseases more so than peripheral fat stores in the subcutaneous space. Epicardial fat has been shown in multiple studies to be directly involved in vascular inflammation of the epicardial coronaries, associated with dysmetabolic syndrome, and implicated in myocardial dysfunction and chamber enlargement. Body mass index, a global measure of excess adiposity, is associated with abnormalities on echocardiography including left atrial dilatation, left ventricular hypertrophy and dilation, and impaired relaxation. These findings suggest that changes in the lipid content within cardiomyocytes themselves is playing a role in these pathologic steps of cardiac remodelling. Obesity-related glomerulopathy has been long-described as a condition of hyperfiltration in obese individuals without diabetes that ultimately leads to CKD. It has been recently shown that massive weight loss does lead to reductions in proteinuria suggesting that this process is reversible. Of note, these salutary changes have been associated with reductions in hs-CRP and improvements in other cardiometabolic parameters including glycemic control. It has been shown that the number of adipocytes in the human body can increase tenfold both in number and in size. With such a dramatic increase in fat mass, cytokines and adipokines are produced in large quantities to assure homeostasis of this expanding organ. Many of these cytokines may cause cardiac and renal injury for example IL-6 and TNF-alpha, which are both secreted by adipocytes. Indeed, the production of IL-6 by abdominal adipocytes into the portal circulation to the liver, is the most important stimulus for release of hs-CRP. Thus, hs-CRP are highest in obese individuals and fall to a greater extent with weight loss than any other intervention. Growth of adipocytes and increase in fatty acid content of visceral locations has been consistently demonstrated to be related to obesity generating diseases more so than peripheral fat stores in the subcutaneous space. Epicardial fat has been shown in multiple studies to be directly involved in vascular inflammation of the epicardial coronaries, associated with dysmetabolic syndrome, and implicated in myocardial dysfunction and chamber enlargement. Body mass index, a global measure of excess adiposity, is associated with abnormalities on echocardiography including left atrial dilatation, left ventricular hypertrophy and dilation, and impaired relaxation. These findings suggest that changes in the lipid content within cardiomyocytes themselves is playing a role in these pathologic steps of cardiac remodelling. Obesity-related glomerulopathy has been long-described as a condition of hyperfiltration in obese individuals without diabetes that ultimately leads to CKD. It has been recently shown that massive weight loss does lead to reductions in proteinuria suggesting that this process is reversible. Of note, these salutary changes have been associated with reductions in hs-CRP and improvements in other cardiometabolic parameters including glycemic control.
Anemia, hypoxiaRAA and sympathetic activationNa and H2O retentionCa and P abnormalitiesHypertension, LVH
AnemiaSodium and H2O retentionUremic solute retentionCa and P abnormalitiesHypertension
Hypovolemic?(functional)
Renal(damage)
Normal ↑Risk Damage ↓GFR Failure Death
Renal(damage + functional)
The Continuum of Renal Damage
Chronic Heart-Kidney Interactions
CRS Type II•Common scenario: longstanding HF leading to progressive CKD (possibly via episodes of AKI)•Key concept: management of sodium and extracellular fluid volume
•Therapies that influence the natural history of HF (effect on CRS?)
–Optimal Na and volume management (diet control)–ACEI, ARB, BB, Aldo blockers, nitrates, hydralazine–Loop diuretics (lower doses have better outcomes)–Optimal hemodynamic control (avoid hyper- and hypotension)–Treatment of anemia and anemia-associated inflammation–Cardiac resynchronization mildly favorable
•Avoidance of added insults to HF and CKD–NSAIDS, Iodinated contrast, Other renal toxic agents
In the European Union diseases of the heart and circulatory system account for 4.3 million deaths a year. The major forms of cardiovascular death are attributable to coronary heart disease and stroke. The economic burden of cardiovascular disease (CVD) in the European Union (EU) in 2006 was 110 billion Euros. Furthermore, the production losses due to morbidity and mortality in the working age population amounted to just under 17 billion Euros.
An estimated 82.6 million Americans suffer from at least one form of cardiovascular disease. Of those, 5.7 million patients carry a diagnosis of heart failure (HF). Hospitalization for heart disease and acute myocardial infarction (AMI) are higher in males, while women are more commonly hospitalized for HF and stroke. The cost burden of CVD and CHF can be quite substantial, nearing $29 billion in 2004 for 1.1 million CHF hospitalizations.
The burden of CHF
Renal perfusion pressure is calculated by the equationmean arterial pressure minus central venous pressure.Decreases in left ventricular systolic or diastolic function,in HF, result in decreased cardiac output, stroke volumeand underfilling of the arterial beds. In HF patients withvolume overload, low systemic pressures combined withincreased central venous or pulmonary artery pressurescan lead to compromise of renal perfusion pressure. Thisdecrease in renal perfusion, coupled with the underlyingatherosclerotic changes due to comorbidities such asdiabetes and hypertension in this particular population,can rapidly worsen any pre-existing renal dysfunction.
The Impact of Congestion
The overall decrease in arterial filling pressures causes releaseof neurotransmitters, including the RAA cascade andproduction of vasoconstrictors (epinephrine and endothelin).Vasoactive agents work to increase peripheral and renalvasoconstriction, leading to decreased RBF and GFR. Theprogressive results of this endogenous neurotransmitter-mediated vasoconstriction are renal hypoxia, cytokine release,inflammation, and over the long course eventual loss ofstructural integrity and function. Neurohormonal abnormalitiesare coupled with altered release of endogenous vasodilatorslike natriuretic peptide and nitric oxide. These processes leadto sodium and fluid retention, along with progressivelydiminishing renal function leading to irreversible kidneydamage.
Impact of neurohormones
Fluid Balance
Daily fluid input:1.5-2.0 L maintenance1.5-2.5 L medications0.8-1.5 L nutrition0.5-1.5 L boluses
Daily fluid output:1.0-2.0 L Urine1.0-2.0 L Insensible losses1.0-3.0 L Dialysis/ UF0.5-1.5 L Other
Acute decompensationAcute heart failureIschemic insultArrythmiasDecreased CO
Hsu, et al. Kidney International 2007
Num
ber p
er 1
00,0
00 p
er y
ears
> 60% increase from 1996 to 2003
Community-based incidence rates of non-dialysis requiring AKI
Community-based incidence rates of dialysis requiring AKI
Hsu, et al. Kidney International 2007
Num
ber p
er 1
00,0
00 p
er y
ears
> 50% increase from 1996 to 2003
AKI is common in dogs too
0
0,2
0,4
0,6
0,8
1
0 10 20 30
ICU Stay (days)
NO ARFn = 1063
ARFn = 348
Prob
abili
ty o
f Sur
viva
l
De Mendonça A et al. Intensive Care Med 26 : 915-921, 2000.
Acute Renal Failure Represents an Independent Risk Factor
Mortality In Acute Renal Failure
Star RA ; Kidney Int (1998); 54: 1817-1831
0
20
40
60
80
100
Isolated ARF* ARF in ICU
% M
orta
lity
* Mortality of isolated ARF has decreased from 80% in 1974 to 9 % in 2003
Acute Interactions%
Mor
talit
y
100
80
60
40
20
0Kidney K + 1 K + 2 K + 3
Number of failing organs
CRS Type III
Disappointing in those without CKD
•Common scenario: AKI leading to HF (probably in patients with an underlying subclinical heart disease), CSAAKI, Contrast-induced AKI leading to LV dysfunction•Key Concept: Na and Water management (other signals such as uremia, cytokines, potassium?)
•Acute Na and volume imbalance (overload or underload)•If Na and volume overload is avoided, will cardiac decompensation be eliminated?
–Early intervention with hemofiltration, SCUF,—trials ongoing•If early bidirectional signaling can be understood, can new preventive targets be developed?
CRS: Conclusions• The cardiorenal syndrome is real and we have a new
definition available• There is insufficient awareness of its implications and of
what we already know• A tsunami of cardiorenal patients is coming• We need to focus our clinical understanding, research
agenda and education on how best to help these patients• Different types of Cardio-Renal Syndrome exist• The new classification will help consistency in prevention,
diagnosis and treatment• Cardio-Renal Syndrome Type 1 is a leading cause of AKI • Biomarkers may represent a corner stone in the evaluation
of these syndromes and in detecting early organ damage making possible prevention of disease progression