Pathophysiology of Cardio-Renal Interactions · Pathophysiology of Cardio-Renal Interactions • Heart-Kidney Interactions: Bidirectional Temporally regulated Mediated by different

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

A widely accepted classification

http://ndt.oxfordjournals.org/content/current�

Cardio-Renal syndromesGeneral Definition:

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


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




Immune mediated damage

Humorally mediated damage


secretion

Acute Kidney Injury



DecreasedperfusionDecreased CO Increased

venous pressure



BNP


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




Immuno mediated damage

Humorally mediated damage


secretion

Exogenous factorsContrast mediaACE inhibitors

Diuretics

Acute Kidney Injury



DecreasedperfusionDecreased CO Increased

venous pressure



BNP


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


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.

Low Cardiac outputNa and fluid overloadChronic hypoperfusionEmbolismVenous CongestionChronic inflammation Cardiac RemodelingEndothelial DysfunctionAcceler. Atherosclerosis

Na and fluid overloadChronic inflammation

Uremic ToxinsMalnutrition

AnemiaEPO resistance

pH abnormalitiesCa-P abmormalities

Lack of VDR activationSoft Tissue calcifications

CKD Progression, ApoptosisNecrosis, Fibrosis, Sclerosis

CARDIO-RENAL CACHEXIA SYNDROMES

CRS TYPES 1- 2 CRS TYPES 3- 4

Non-oedematous weight loss of >6% of total body weight over a period of 6

or more months

Malnutrition, loss of >10% of lean tissue or percent

of ideal weight <90% .

Heart Failure, Systolic/diastolicdysfunction, Myoc.Remodelling

Cardio-Renal SyndromeAnemia and Iron deficiency

⇑ Cardiac Work⇑ Cardiac Output

⇑ Arterial diameter and volume⇑ Arterial wall tension

Eccentric remodelling of the

arterial system

⇑ Left ventricle hypertrophy⇑ Left Ventricle wall tension

Left ventricle eccentric

remodelling

Reduced Blood ViscosityDecreased Oxygen Delivery

Increased Sympathetic ActivityHyperdynamic circulation

AKI

AKI CKD

CKD

Cardio-Renal SyndromeCKD and UREMIA

CKD

Acquired Risk factorsPrimary nephropathy

AnemiaUremic toxinsCa/P abnormalitiesNutritional status, BMINa – H2O overloadChronic Inflammation

Anemia & malnutritionCa/P abnormalitiesNa – H2O overloadUnfriendly milieuInflammation

Sclerosis -Fibrosis

Glomerular--interstitialdamage

CHF

↑ Bone remodeling

↑ Acute phase reactants

↑ Muscle catabolism

↑ Endothelial dysfunction↑ Monocyte adhesion↑ Smooth muscle cell proliferation↑ LDL oxidation↑Vascular calcification↑ Oxidant stress

↓ Appetite↑ REE

↑Adipocytokine production

↑ Insulin resistance

↓ Fetuin-A

Uremia retention products

Cardio-Renal SyndromeThe unfriendly uremic milieu

http://www.endocrineweb.com/images2/pancr.gif�

24%

38%

53%

29%

16%

Krumholz HM et al. Am J Cardiol. 2000;85:1110.

≤

Risk of Cardiorenal Syndrome by Number of Risk Factors

≥

Chronic Cardio-Renal Syndrome (Type 2) a condition close to veterinary pathophysiology

Chronic Heart

Disease

Increasedsusceptibility

to insults

Insult and Initiation of

kidney damage

Progressionof CKD

Chronic hypoperfusionIncreased renal vascular resistanceIncreased venous pressureEmbolism

Genetic risk factorsAcquired Risk factorsLow cardiac output (CO)

AnemiaSodium and H2O retentionUremic solute retentionCa and P abnormalitiesHypertension

Sclerosis - Fibrosis

Chronic hypoperfusionApoptosis

Low cardiac output (CO)Subclinical inflammationEndothelial dysfunctionAccelerated atherosclerosis

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

Body Composition

Fluid Balance

Ris

k of

Com

plic

atio

nsRestrictive Fluid protocols

Dehydration

Liberal Fluid protocols

Overhydration

HypotensionTachycardiaShockOrgan hypoperfusionOliguriaRenal Dysfunction

Optimal Status

HypertensionPeripheral EdemaImpaired pulmonary exchanges

Organ CongestionRenal Dysfunction

ProceduresDrugs

DialysisNormal Heart

Diseased Heart

Acute Reno-Cardiac Syndrome (Type 3)

Acute Heart

Dysfunction

Glomerular diseasesInterstitial diseasesAcute tubular necrosisAcute pyelonephritisAcute urinary obstruction

Acute Kidney Injury

BIOMARKERSTroponinMyoglobinMPOBNP

Humoral Signalling Cytokine

secretion

Hypertension


Caspase activationApoptosisMonocyte

Activation

Electrolyte, acid-base& coagulation imbalances

Volume expansion

Decreased GFR

Increased pre-load

Na + H2O retention


RAA activation,, vasoconstriction

Endothelial activation

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?

–ET receptor antagonists–Vasopressin receptor antagonists–Natriuretic peptides–Adenosine receptor antagonists

Chronic Reno-Cardiac Syndrome (Type 4)

Cardiac remodelling Neurohormonal abnormalitiesIncreased ischemic riskLeft ventricular hypertrophyLeft diastolic dysfunctionDecreased coronary perfusionInflammationCoronary and tissue calcification

CKD Stage 1-2

CKD Stage 3-4

CKD Stage 5-Dialysis

Genetic risk factorsAcquired risk factorsPrimary nephropathyDiabetes mellitus

SmokingObesityHypertensionDyslipidemiaHomocysteinemiaChronic inflammation

BIOMARKERSCardiac troponinNatriuretic peptidesAsymmetric dimethylarginineIschemia modified albuminAcute phase proteinsSerum amyloid protein AC-reactive protein

AnemiaUremic toxinsCa and P abnormalitiesNutritional status, BMISalt and water overloadChronic Inflammation

Anemia & malnutritionCa/Phos abnormalitiesSoft tissue calcificationNa – H2O overloadEPO resistanceUremic toxins

↓ Appetite↑Adipocytokine

production

Chronic Inflammation

Cytokine production

Endothelial dysfunctionSmooth muscle proliferationLDL oxidationVascular calcificationOxidant stressAccelerated atherosclerosis Acute phase

reactants

↑ Insulin resistance

Bone remodeling ↑ Muscle

catabolism

monocyte stimulation

Artificial surfacesContaminated fluids

Sclerosis - Fibrosis

Glomerular/interstitialdamage

http://www.endocrineweb.com/images2/pancr.gif�

CHRONIC INFLAMMATION

IN HEMODIALYSIS

UremiaMembrane

Comorbid State Dialysate Purity

R. O. S.Production

AntiOxDefense

Oxidative Stress

Access & Procedure

Secondary Cardio-Renal Syndrome (Type 5)

Systemic diseasesDiabetesAmyloidosisVasculitisSEPSIS

Organ damage/dysfunction

hypoxiaoxidative

stresstoxemia

Hemodynamic changesHypoperfusion

perfusion pressure ↓, RVR ↑Hischemia/ reperfusion

Exogenous toxins heme proteins

antibiotics, contrast media

LPS / endotoxin Monocyte activation

cytokines

Renal Insufficiency

Heart failure

Sympathetic system activationNeurohumoral stress

Inflammation

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

Documents

Pathophysiology of Cardio-Renal Interactions · Pathophysiology of Cardio-Renal Interactions • Heart-Kidney Interactions: Bidirectional Temporally regulated Mediated by different