Le sindromi cardio‐renali

G. VESCOVO

G. VESCOVO MD, PhD, FESCDip. Medicina InternaVICENZA

Le sindromi cardio‐renali

Consensus Conference

Prevalence of CVDAny CVD: 80 million (1 in 3)Htn: 73 million CAD: 16 millionAMI: 8.1 millionCHF: 5.3 millionStroke: 5.8 millionCongenital: 0.6-1.3 million

AHA/ACC Circulation 2008

Prevalence of CVD and CKD

N Engl J Med 2010

AHA/ACC Circulation 2008

CKD in CVD28.2%!

Prevalence of CVD and CKD

0

20

40

60

CADFG ≤60 mL/min

AMI FG <60 mL/min

CHFFG ≤60 mL/min

23%

46%

33%

Patie

nts

With

CK

D (%

)CKD and CVD

Coresh, et al., 2007

Hearth and Kidney: a liaison dangereuse

Regulation of volume and BP (Na+ and H2O)Electrolyte and acid-base balanceHormonal function (Erythropoiesis – Vascular tone – Ca/P)Blood Purification from metabolic waste products

Regulation of perfusion pressure and flows to peripheryElectrical activity dependent on electrolytes and acid-baseContractility depending on O2, volume, electrolytes, toxin Hormonal function (ANP - BNP)

The Cardiorenal Syndrome

There is no commonly accepted definition Term borrowed from other areas (e.g. Hepatorenal Syndrome, the same kidney in another individual would perform normally). Fix the heart, and get the kidney back to normal!

General term used to define heart‐kidney pathological interactions

It is a pathophysiological entity that describes the initiation and progression of renal insufficiency (RI) secondary to heart failure(HF); however it also includes the negative effects of reduced renal function on heart function. 

It should include the damage/dysfunction induced to one of the two organs by an acute or chronic dysfunction of the other organ.

Cardiorenal or renocardiac syndrome?  Acute or chronic?

C‐R

R‐C

Chronic Acute

The need for a consensus classification and definition that describes all the clinicalconditions together with the bidirectional nature of the organ cross‐talk emerges clearly.

Bidirectionality and time windowCardiorenal syndromes: to indicate the presence of multiple syndromesSubtypes: to recognize primary organ dysfunction (cardiac vs. renal) and the time frameof the insult (acute vs. chronic)

What is cardiorenal syndrome?

What is it cardiorenal syndrome? How can we define it? What are the types? How do they impact the clinical outcomes? Why is early diagnosis important? What is the role of new biomarkers?

Definitions of the 5 subtypes

of cardio-renal syndrome

Acute HeartDisease

orProcedures

Renal hypotperfusionRed. Oxigen deliveryNecrosis / apoptosisDrop in GFRResistance to ANP/BNP

BIOMARKERSCreatinine Cystatin‐CN‐GALKIM‐1

Hemodynamically mediated damage

Immuno mediated damage

Humorally mediated damage

ACUTE CARDIO‐RENAL SYNDROME:  TYPE 1

Humoral Signalling

Cytokine secretion

Exogenous FactorsContrast mediaACE inhibitors

Diuretics

Acute KidneyInjury

Caspase activationApoptosis

Caspase activationApoptosis

Arterial underfilling

Acute decompensationIschemic insultCoronary angiographyCardiac Surgery

Drop in CO Incr. venous pressure

Toxicity Vascocostr.

RAA activation, Na + H2O retention, vasoconstriction

Imbalance between ET and EDNO 

BNP

Sympathetic Activation

Hormonal Factors

Monocyte Activation Endothelial 

activation

ltx, ET, Tx

27-40% of patiets hospitalized for acute de-compensated HF develop acute kidney injury

Chronic HeartDisease

Increasedsusceptibilityto insults

Insult and Initiation of

kidney damage

Progressionof CKD

Chronic hypoperfusionIncreased renal vasc. resist.Increased venous pressureEmbolism

Genetic risk factorsAcquired Risk factorsLow cardiac output (CO)

AnemiaSodium and H2O retentionUremic solute retentionCa and P abnormalitiesHypertension

Sclerosis ‐ Fibrosis

Chronic hypoperfusionNecrosis ‐ apoptosis

Low cardiac output (CO)Subclinical inflammationEndothelial dysfunctionAccelerate atherosclerosis

Anemia, hypoxiaRAA and sympathetic act.Na and H2O retentionCa and P abnormalitiesHypertension, LVH

AnemiaSodium and H2O retentionUremic solute retentionCa and P abnormalitiesHypertension

CHRONIC CARDIO‐RENAL SYNDROME:  TYPE 260% of patients hospitalized with congestive HF have chronic kidney disease

ACUTE RENO‐CARDIAC SYNDROME:  TYPE 3

Acute     HeartDysfunction

Glomerular diseasesInterstitial diseasesAcute tubular necrosisAcute pyelonephritisAcute urinary obstruction

Acute Kidney Injury

Acute decompensationAcute heart failureHischemic insultArrythmiasDrop in CO

BIOMARKERSTroponinMyoglobinMPOBNP

Humoral Signalling

Cytokine secretion

Hypertension

Caspase activationApoptosis

Caspase activationApoptosisMonocyte 

Activation

Electrolyte,  acid‐base& coagulation imbalances

Volume expansion

Drop in GFR Increased pre‐load

Na + H2O retention

Sympathetic Activation

RAA activation,, vasoconstriction 

Endothelial activation

CHRONIC RENO‐CARDIAC SYNDROME:  TYPE 4

Cardiac remodelling Neurohormonal abnormalitiesIncreased hischemic riskLeft ventricular hypertrophyLeft diastolic dysfunctionDecreased coronary perfusionStunning MyocardiumHemodynamic worseningInflammationCoronary and tissue calcification

CKD Stage 1‐2

CKD Stage 3‐4

CKD Stage 5‐

Dialysis

Genetic risk factorsAcquired Risk factorsPrimary nephropathyDiabetes mellitus

Smoke‐ ObesityHypertensionDyslipidemiaHomocystein levelsChronic inflammation

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

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

Anemia & malnutritionCa/P abnormalitiesSoft tissue calcificationNa – H2O overloadEPO resistanceUremic toxinsUnfriendly milieu

↓ 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

SECONDARY CARDIO‐RENAL SYNDROME:  TYPE 5

Systemic diseasesDiabetesAmyloidosisVasculitisSEPSIS

Organ damage/dysfunction

hypoxiaox stresstoxemia

Hemodynamic changesHypoperfusion

perfusion pressure ↓, RVR ↑Hischemia/ reperfusion 

Exogenous toxins heme proteins antibiotics, contrast media, vasopressors

LPS / endotoxin Monocyte activation

cytokines

Renal Insufficiency

Heart failure

Sympathetic system activationNeurohumoral stress

Inflammation

The Cardiorenal Syndrome Assessment and Diagnosis

A new definition of cardiorenal syndrome with a comprehensive classification into five different subtypes is available

We need to use the new definition/classification to have a standard terminology in clinical settings and new clinical trials.

We need to evaluate the impact of early biomarkers on diagnosis and various therapeutic approaches.

We need to focus on biomarker profiles to identify patients at risk for any negative cardiorenal interaction. 

We need to appraise current evidence and generate wise recommendations for practice and when evidence is missing, we need to create a research agenda to fill the gaps and generate the missing evidence

A biomarker is a biological compound, objectively measurable, evaluated as an indicatorof normal/pathological biological processes, or pharmacologic response to therapeuticintervention.

Urine  

Plasma

IL‐18

NGAL

Using cDNA microarray as a screening technique, a subset of genes whose expression is up‐regulated within the first few hours after renal injury can be discovered. (Or early  GFR)

Biomarkers

UrinePlasma

Cystatin‐C

Neutrophil gelatinase‐associated lipocalin

Pharmacologic therapy in patients with CRS: a complex issue

Coexistence of kidney with heart disease has major implications:

• renal function alters the pharmacochinetics and pharmacodinamics of several cardio-active medications requiring drug dosage adjusments

• certain CV drugs can interfere with renal function and must admistered with caution to patients with underlying kidney disease

• patients with kidney disease have been underrepresented in CVD clinical trials

Indication Intended action and effects

Side effects and problems

ACE inhibitors and ARBS

Acute CRS

No compelling indication according to ESC guidelines [1]No consensus on timing for initiation.Treatment should be continued whenever possible in those already treatedTreatment to be initiated before hospital discharge

Deterioration of kidney function if already on boardHypotension

Chronic CRS Life savings, reduce morbidityPrevent cardiac remodellingARBS as an alternative only in patients intolerant to ACEIs

Monitor kidney function and electrolytesHypotension

Acute RCS - Contraindicated in renal artery stenosis

Chronic RCS Nephroprotection RAAS antagonismDecrease proteinuria

Mild transient deterioration of kidney functionCareful monitoring in dialysis patients (hypotension)

Beta-blockers Indication Intended action and effects

Side effects and problems

Acute CRS

Dose may need to be reduced temporarily, in general should not be withdrawn unless signs of low output

Hypotension, bradyarrhythmias

Chronic CRS

Life savingsReduce morbidityPrevent remodelling

Hypotension, bradyarrhythmiasDeterioration in heart failure symptoms (transient) Asthma

Chronic RCS

Cardioprotectionand prevention of tachyarrhythmias

As above

Diuretics Indication Intended action and effects

Side effects and problems

Acute CRS

Natriuresis, reduction of fluid overload, Na and H2O eliminationFrusemide preferred

Potential hypovolemiaand worsening of renal failure

Chronic CRS

control of diuresis and extracellular fluid volume Symptoms relief

Volume depletion HypotensionWorsening renal failure, hyperuricemia, K imbalance. Diuretic resistance

Acute RCS Maintenance of non oliguric AKIFrusemide preferred

No evidence for renal protection nor reduction of need for RRT

Chronic RCS

Maintenance of diuresis in CKD 4 and 5. Control of hypertension and fluid balance

Potential toxic effects

Secondary CRS

Maintenance of diuresis and fluid balance

Direct and cumulative toxicity with other drugs (antibiotics- anti inflammatory)

Digoxin Indication Intended action and effects

Side effects and problems

Chronic CRS and Chronic RCS

Reduce HF HospitalisationImprove symptoms Mortality unchanged

Toxicity if reduced GFRAdjust dosage

Acute CRS

If high heart rate AF is present

As above

G. VESCOVO  Medicina InternaVICENZA

CONCLUSIONS

• Cardiologists and nephrologists and internists need to talk each other• The way they should do that is by a systematic and common approach•The classification of cardiorenalsyndromes is an attempt to bring thisview into the clinical setting

G. VESCOVO  Medicina InternaVICENZA

G. VESCOVO  Medicina InternaVICENZA

18% of 11.327 pts admitted to 115 hospitals in the EuroHeart Failure SurveyProgram, had renal dysfunction.(Cleland JGF,Eur Heart J 2003;24:442‐463)

Between 30% and 50% of patients with congestive heart failure present aimpaired renal function.(Obialo Am J Cardiol 2007).

30% of hospitalized pts for heart failure had a history of chronic renal insufficiencyand 20% a serum creatinine level > 2 mh/dL in an evaluation of 105.388hospitalizations episodes o at 274 hospitals from the Acute Decompensated HeartFailure National registry (ADHERE). (Adams KF,Am Heart J2005;149:209‐216)

The prevalence of patients who develop during hospitalization for decompensatedheart failure a worsening renal function is about 25%,according to a systematicreview and meta‐analysis .

Cardiologist point of view

“In the general population, about one person in 20 has a serum creatinine levelabove normal, signifying mild kidney disease “(Zoccali Nephrol Dial Transplant 2002)

“Mortality in end stage renal disease and chronic kidney disease patients is duefor about 50% to cardiovascular comorbidity “(Zoccali Nephrol Dial Transplant 2002).

“In the 45‐54 year age group cardiovascular mortality rate in dialysis patients isabout 65 times higher than in the general population. In younger cohortscardiovascular mortality rate is 500 times higher than in the general population.”(Levey Am J Kidey disease 1998)

Nephrologist point of view

Heart‐Kidney Pathologic Interactions

Cardiovascular mortality increased by end stage renal dysfunction (ESRD)Cardiovascular risk increased by kidney dysfunctionChronic HF progression due to kidney dysfunction• Uremia related HF• Volume related HF

HF due to acute kidney dysfunction• Volume/uremia‐induced HF• Renal ischemia‐induced HF• Sepsis/cytokine induced HF

CKD secondary to HFAKI secondary to contrast induced nephropathy (CIN)AKI secondary to cardiopulmonary bypass (CPB)AKI secondary to heart valve replacementAKI secondary to HF

The syndrome of Heart Failure

CHFLeft VentricularDysfunction

CongestionLungsLimbsGuts

DyspnoeaFatigue

Arrhythmias

ACUTE

CHRONIC

Renal dysfunction is common in patients with acute decompensated HF

0

10

20

30

40

50

<15 15-29 30-59 60-89 >90Estimated GFR, ml/min

Patien

ts (%)

Heywood et al. Heart Failure Reviews 2004;9:195-201

80% of patients have at leaststage CKD 3

RIFLE Criteria for Acute Renal Dysfunction

Risk

Injury

Failure

Loss

ESRD End Stage Renal Disease

GFR Criteria* Urine Output Criteria

UO < .3ml/kg/hx 24 hr or Anuria x 12 hrs

UO < .5ml/kg/hx 12 hr

UO < .5ml/kg/hx 6 hr

Increased creatinine x 2or GFR decrease >

50%

Increase creatinine x 3or GFR dec >75%

or creatinine ≥4mg/dl(Acute rise of ≥0.5 mg/dl)

HighSensitivity

HighSpecificity

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

ADQIADQI

Increased creatinine x1.5or GFR decrease >

50%

R (I)

I (II)

F (III))

Increased creatinine x1.5OR > 0.3mg/dl

UO < .3ml/kg/hx 24 hr or Anuria x 12 hrs

UO < .5ml/kg/hx 12 hr

UO < .5ml/kg/hx 6 hr

Increased creatinine x2

Increase creatinine x3or creatinine ≥4mg/dl

(Acute rise of ≥0.5 mg/dl)

HighSensitivity

HighSpecificity

RRT Started

Modifications proposed by AKIN

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

RIFLE max

Hoste et al. Crit Care. 2006;10(3):R73

Acute Interactions% M

ortality

100

80

60

40

20

0

Kidney K  +  1 K  +  2 K  +  3

Number of failing organs

Prevalence/Incidence Estimates

2007Any CVD: 80 million (1 in 3)Htn: 73 million CAD: 16 millionAMI: 8.1 millionCHF: 5.3 millionStroke: 5.8 millionCongenital: 0.6-1.3 million

AHA/ACC Circulation 2008

2007Any CKD (≥Stage I) 16.8%CKD Stage I ~ 5.7%CKD Stage II ~ 5.4%CKD III ~ 5.4%Stage IV-V ~ 0.4%ESKD 2x increase in 10 years(261/million to 348/million)Projected to increase 16%

Pts with Heart Failure :recurrent and  frequent hospitalization for symptoms and treatment; over 1 million of hospitalizations annually which generate 6.5 million inpatient hospital  days per yrApproximately 20% to 40% of patients admitted to  a hospital for acute heart failure have comorbidrenal insufficency, based on clinical history and serum creatinine levels(1.681 pts admitted at 18 hospitals in Connecticut:21% had baseline renal  failure and 41% had a baseline serum creatinine level ≥ 1.5 mg/dL )

Inotropic AgentsDopamine DobutamineLevoximendanMilrinoneEnoximone

Acute CRS To increase cardiac output in low output if proven or to maintain blood pressureSome inotropic agents may decrease peripheral resistances

Arrhythmias;Receptor desensitization with prolonged use;Some may adversely affect outcome

VasopressorsEpinephrineNorepinephrine

Acute CRS Norepinephrine indicated only in cardiogenic shock when other inotropic therapies failEpinephrine indicated only as rescue therapy for cardiac arrest, not as an inotrope

VasodilatorsNitroprussideNitrates

Acute CRS

Indicated if organ congestion is presentIncrease renal and peripheral blood flow

Hypotension especially in hypovolemic patients;Cyanide intoxication for nitroprusside

NesiritideAcute CRS

BNP analogue VasodilatorData on mortality Uncertain

Hypotension Can worsen kidney function, but data uncertain

Vasopressin Antagonists

Acute CRS

symptoms relief, promote water elimination and weight loss in the short term

No changes in mortality and morbidity at one year with tolvaptan

EndothelinAntagonists

Chronic CRS and Chronic RCS

Aimed to block endothelin II mediated vasoconstriction

No changes in mortality Currently licensedonly forPulmonaryhypertension withRV failure toimprove EC

Adenosine A1-receptorantagonists

Acute and chronic CRS

Block adenosine glomerular vasoconstrictionMay improve symptoms and prevent deterioration in renal function

Weight loss?

Cardio-Renal Syndromes (CRS) General Definition:Disorders of the heart and kidneys whereby acute or chronic dysfunction in

one organ may induce acute or chronic dysfunction of the other

Acute Cardio-Renal Syndrome (Type 1)Acute worsening of cardiac function leading to renal dysfunction

Chronic Cardio-Renal Syndrome (Type 2)Chronic abnormalities in cardiac function leading to renal dysfunction

Acute Reno-Cardiac Syndrome (Type 3)Acute worsening of renal function causing cardiac dysfunction

Chronic Reno-Cardiac Syndrome (Type 4)Chronic abnormalities in renal function leading to cardiac disease

Secondary Cardio-Renal Syndromes (Type 5)Systemic conditions causing simultaneous dysfunction of the heart and

kidney

MorphineAcute CRS

Relief of dyspnoea, chest pain, helps NIV

Respiratory depression

Syndromes

Organ failure sequence

Possible Definition

Abrupt worsening of cardiac function leading to acute kidney injury

Chronic abnormalities in cardiac function causing progressive and permanent chronic kidney disease

Abrupt worsening of renal function causing acute cardiac disorders

CKD contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of cardiovascular events

Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction

Primary events

Acute decompensated heart failure, ischemic insult, coronary angio, cardiac surgery

LV remodeling and dysfunctionDiastolic dysfunctionChronic abnormalities in cardiac function

AKI (e.g. acute kidney ischaemia or glomerulonephritis)

CKD(e.g. chronic glomerular disease)

Sepsis

Possible Criteria for primary events

Severe arrythmiaTroponin/ ST elevationECHO: dilatation

Decreased EFIncreased CVPNYHF class 3-4

RIFLE R.I.F. or AKIN stage 1-2-3 or AKI requiring RRT

CKD stage 1-5 or CKD requiringRRT

APACHE 2 > SOFA SCORE >N. of failing organs

Sequelae Inadequate renal perfusionReduced diuretic responsivenessWorsening renal function

Nephroangiosclerosis, chronicintesrt. Nephr.

ADHF, severe arrythmias, shock LVH, Dilatativemyocardiopathy, CHF

ADHF - AKI

Possible Criteria for sequelae

RIFLE R,I,F by creatinine or urine output.

CKD stage 1-5 Pulmonary edema, electrolyteimbalance arrythmias, cardiacarrest, reduced myocardiaccontractility ADHF, AHF, pericarditis

CHF Decreased EFIncreased CVPNYHF class 3-4

RIFLE R,I,F or RRT

Cardiac markers

Troponin, BNP, MPO BNP, CRP BNP, CRP CRP CRP, procalcitonin,

Renal Markers

Serum Cystatine, Creatinine, NGAL. Urinary KIM-1, IL-18, NGAL, NAG

Creatinine, Cystatic C, Urea, Uric Acid, CRPDecreased GFR

Serum Cystatine, Creatinine, NGAL. Urinary KIM-1, IL-18, NGAL, NAG

Creatinine, Cystatic C, Urea, Uric Acid CRPDecreased GFR

Creatinine, NGAL, IL-18, KIM-1, NAG

Systemic Disease

Type 1Acute Cardiorenal

Type 2Chronic Cardiorenal  

Type 3Acute Renocardiac

Type 4Chronic Renocardiac

Type 5Secondary

Kidney Injury ContinuumVaidya VS, Ferguson MA, Bonventre JV. Biomarkers of Acute Kidney Injury.

Annu Rev Pharmacol Toxicol 2008;48:463‐493

Biomarkers(predictors)

Biomarkers(preventionprotection) Biomarkers (therapy)

Conceptual Model for AKI

MOLECULAR CELLULAR BIOMARKER CLINICAL

Multiple Timezone Organ Damage Clock Display

Analyze Biology by Time‐Zones with Adequate and Precision Clocks

we can identify different milestones along the timeline of AKI. Injury begins inducing molecular modifications subsequently evolving into cellular damage. Cells start to produce biomarkers of injury and only later does the clinical picture of the syndrome develop with the typical sign and symptoms.