Le sindromi cardio renali G. VESCOVO

Le sindromi cardio renali G. VESCOVO

G. VESCOVO MD, PhD, FESC Dip. Medicina Interna VICENZA Le sindromi cardio renali

Consensus Conference

Prevalence of CVD Any CVD: 80 million (1 in 3) Htn: 73 million CAD: 16 million AMI: 8.1 million CHF: 5.3 million Stroke: 5.8 million Congenital: 0.6-1.3 million Prevalence of CVD and CKD AHA/ACC Circulation 2008 N Engl J Med 2010

Prevalence of CVD and CKD CKD in CVD 28.2%! AHA/ACC Circulation 2008

CKD and CVD 60 Patients With CKD (%) 40 20 23% 33% 46% 0 CAD FG 60 ml/min AMI FG <60 ml/min CHF FG 60 ml/min Coresh, et al., 2007

Hearth and Kidney: a liaison dangereuse Regulation of volume and BP (Na + and H 2 O) Electrolyte and acid-base balance Hormonal function (Erythropoiesis Vascular tone Ca/P) Blood Purification from metabolic waste products Regulation of perfusion pressure and flows to periphery Electrical activity dependent on electrolytes and acid-base Contractility depending on O 2, 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?

Chronic Acute C R R C The need for a consensus classification and definition that describes all the clinical conditions together with the bidirectional nature of the organ cross talk emerges clearly. Bidirectionality and time window Cardiorenal syndromes: to indicate the presence of multiple syndromes Subtypes: to recognize primary organ dysfunction (cardiac vs. renal) and the time frame of 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 CARDIO RENAL SYNDROME: TYPE 1 27-40% of patiets hospitalized for acute de-compensated HF develop acute kidney injury Hemodynamically mediated damage Drop in CO Arterial underfilling Incr. venous pressure Acute Heart Disease or Procedures Acute decompensation Ischemic insult Coronary angiography Cardiac Surgery Caspase activation Apoptosis Humoral Signalling BNP Exogenous Factors Contrast media ACE inhibitors Diuretics Sympathetic Activation Humorally mediated damage RAA activation, Na + H2O retention, vasoconstriction Imbalance between ET and EDNO Hormonal Factors Immuno mediated damage Monocyte Activation Endothelial activation Toxicity Vascocostr. ltx, ET, Tx Cytokine secretion Caspase activation Apoptosis Renal hypotperfusion Red. Oxigen delivery Necrosis / apoptosis Drop in GFR Resistance to ANP/BNP BIOMARKERS Creatinine Cystatin C N GAL KIM 1 Acute Kidney Injury

CHRONIC CARDIO RENAL SYNDROME: TYPE 2 60% of patients hospitalized with congestive HF have chronic kidney disease Anemia Sodium and H2O retention Uremic solute retention Ca and P abnormalities Hypertension Increased susceptibility to insults Genetic risk factors Acquired Risk factors Low cardiac output (CO) Chronic hypoperfusion Necrosis apoptosis Chronic Heart Disease Low cardiac output (CO) Subclinical inflammation Endothelial dysfunction Accelerate atherosclerosis Insult and Initiation of kidney damage Anemia, hypoxia RAA and sympathetic act. Na and H2O retention Ca and P abnormalities Hypertension, LVH Anemia Sodium and H2O retention Uremic solute retention Ca and P abnormalities Hypertension Chronic hypoperfusion Increased renal vasc. resist. Increased venous pressure Embolism Sclerosis Fibrosis Progression of CKD

ACUTE RENO CARDIAC SYNDROME: TYPE 3 Drop in GFR Na + H 2 O retention Volume expansion Increased pre load Hypertension Acute Kidney Injury Sympathetic Activation RAA activation,, vasoconstriction Acute Heart Dysfunction Glomerular diseases Interstitial diseases Acute tubular necrosis Acute pyelonephritis Acute urinary obstruction Humoral Signalling Electrolyte, acid base & coagulation imbalances Cytokine secretion Acute decompensation Acute heart failure Hischemic insult Arrythmias Drop in CO Caspase activation Apoptosis Monocyte Activation Endothelial activation Caspase activation Apoptosis BIOMARKERS Troponin Myoglobin MPO BNP

CKD Stage 1 2 Glomerular/interstitial damage CKD Stage 3 4 CHRONIC RENO CARDIAC SYNDROME: TYPE 4 Genetic risk factors Acquired Risk factors Primary nephropathy Diabetes mellitus Anemia Uremic toxins Ca/P abnormalities Nutritional status, BMI Salt and water overload Chronic Inflammation Smoke Obesity Hypertension Dyslipidemia Homocystein levels Chronic inflammation Cardiac remodelling Neurohormonal abnormalities Increased hischemic risk Left ventricular hypertrophy Left diastolic dysfunction Decreased coronary perfusion Stunning Myocardium Hemodynamic worsening Inflammation Coronary and tissue calcification Sclerosis Fibrosis CKD Stage 5 Dialysis Endothelial dysfunction Smooth muscle proliferation LDL oxidation Vascular calcification Oxidant stress Accelerated atherosclerosis Bone remodeling Artificial surfaces Contaminated fluids Muscle catabolism Anemia & malnutrition Ca/P abnormalities Soft tissue calcification Na H2O overload EPO resistance Uremic toxins Unfriendly milieu Appetite monocyte stimulation Acute phase reactants Chronic Inflammation Cytokine production Adipocytokine production Insulin resistance BIOMARKERS Cardiac troponin Natriuretic peptides Asymmetric dimethylarginine Ischemia modified albumin Acute phase proteins Serum amyloid protein A C reactive protein

SECONDARY CARDIO RENAL SYNDROME: TYPE 5 Heart failure Sympathetic system activation Neurohumoral stress Inflammation Systemic diseases Diabetes Amyloidosis Vasculitis SEPSIS Hemodynamic changes Hypoperfusion perfusion pressure, RVR Hischemia/ reperfusion hypoxia ox stress toxemia Exogenous toxins heme proteins antibiotics, contrast media, vasopressors Organ damage/dysfunction LPS / endotoxin Monocyte activation cytokines Renal Insufficiency

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 indicator of normal/pathological biological processes, or pharmacologic response to therapeutic intervention. Urine Plasma

Biomarkers IL 18 Cystatin C NGAL Neutrophil gelatinase associated lipocalin Plasma Urine 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)

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

ACE inhibitors and ARBS Indication Acute CRS Chronic CRS Intended action and effects No compelling indication according to ESC guidelines [1] No consensus on timing for initiation. Treatment should be continued whenever possible in those already treated Treatment to be initiated before hospital discharge Life savings, reduce morbidity Prevent cardiac remodelling ARBS as an alternative only in patients intolerant to ACEIs Side effects and problems Deterioration of kidney function if already on board Hypotension Monitor kidney function and electrolytes Hypotension Acute RCS - Contraindicated in renal artery stenosis Chronic RCS Nephroprotection RAAS antagonism Decrease proteinuria Mild transient deterioration of kidney function Careful monitoring in dialysis patients (hypotension)

Beta-blockers Indication Intended action and effects Acute CRS Chronic CRS Chronic RCS Dose may need to be reduced temporarily, in general should not be withdrawn unless signs of low output Life savings Reduce morbidity Prevent remodelling Cardioprotection and prevention of tachyarrhythmias Side effects and problems Hypotension, bradyarrhythmias Hypotension, bradyarrhythmias Deterioration in heart failure symptoms (transient) Asthma As above

Diuretics Indication Intended action and effects Acute CRS Chronic CRS Acute RCS Chronic RCS Secondary CRS Natriuresis, reduction of fluid overload, Na and H2O elimination Frusemide preferred control of diuresis and extracellular fluid volume Symptoms relief Maintenance of non oliguric AKI Frusemide preferred Maintenance of diuresis in CKD 4 and 5. Control of hypertension and fluid balance Maintenance of diuresis and fluid balance Side effects and problems Potential hypovolemia and worsening of renal failure Volume depletion Hypotension Worsening renal failure, hyperuricemia, K imbalance. Diuretic resistance No evidence for renal protection nor reduction of need for RRT Potential toxic effects 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 Hospitalisation Improve symptoms Mortality unchanged Toxicity if reduced GFR Adjust dosage Acute CRS If high heart rate AF is present As above

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 cardiorenal syndromes is an attempt to bring this view into the clinical setting G. VESCOVO Medicina Interna VICENZA

G. VESCOVO Medicina Interna VICENZA

G. VESCOVO Medicina Interna VICENZA

Cardiologist point of view 18% of 11.327 pts admitted to 115 hospitals in the EuroHeart Failure Survey Program, had renal dysfunction. (Cleland JGF,Eur Heart J 2003;24:442 463) Between 30% and 50% of patients with congestive heart failure present a impaired renal function. (Obialo Am J Cardiol 2007). 30% of hospitalized pts for heart failure had a history of chronic renal insufficiency and 20% a serum creatinine level > 2 mh/dl in an evaluation of 105.388 hospitalizations episodes o at 274 hospitals from the Acute Decompensated Heart Failure National registry (ADHERE). (Adams KF,Am Heart J 2005;149:209 216) The prevalence of patients who develop during hospitalization for decompensated heart failure a worsening renal function is about 25%,according to a systematic review and meta analysis.

Nephrologist point of view In the general population, about one person in 20 has a serum creatinine level above normal, signifying mild kidney disease (Zoccali Nephrol Dial Transplant 2002) Mortality in end stage renal disease and chronic kidney disease patients is due for about 50% to cardiovascular comorbidity (Zoccali Nephrol Dial Transplant 2002). In the 45 54 year age group cardiovascular mortality rate in dialysis patients is about 65 times higher than in the general population. In younger cohorts cardiovascular mortality rate is 500 times higher than in the general population. (Levey Am J Kidey disease 1998)

Heart Kidney Pathologic Interactions CKD secondary to HF AKI secondary to contrast induced nephropathy (CIN) AKI secondary to cardiopulmonary bypass (CPB) AKI secondary to heart valve replacement AKI secondary to HF Cardiovascular mortality increased by end stage renal dysfunction (ESRD) Cardiovascular risk increased by kidney dysfunction Chronic 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

The syndrome of Heart Failure Dyspnoea Fatigue Left Ventricular Dysfunction CHF Congestion Lungs Limbs Guts Arrhythmias

ACUTE CHRONIC

Renal dysfunction is common in patients with acute decompensated HF 50 80% of patients have at least stage CKD 3 Patients (%) 40 30 20 10 0 <15 15-29 30-59 60-89 >90 Estimated GFR, ml/min Heywood et al. Heart Failure Reviews 2004;9:195-201

ADQI RIFLE Criteria for Acute Renal Dysfunction ADQI GFR Criteria* Urine Output Criteria Risk Increased creatinine x1.5 or GFR decrease > 50% UO <.5ml/kg/h x 6 hr High Sensitivity Injury Increased creatinine x 2 or GFR decrease > 50% UO <.5ml/kg/h x 12 hr Failure Increase creatinine x 3 or GFR dec >75% or creatinine 4mg/dl (Acute rise of 0.5 mg/dl) UO <.3ml/kg/h x 24 hr or Anuria x 12 hrs High Specificity Loss ESRD Persistent ARF** = complete loss of renal function > 4 weeks End Stage Renal Disease

Modifications proposed by AKIN R (I) Increased creatinine x1.5 OR > 0.3mg/dl UO <.5ml/kg/h x 6 hr High Sensitivity I (II) Increased creatinine x2 UO <.5ml/kg/h x 12 hr F (III)) Increase creatinine x3 or creatinine 4mg/dl (Acute rise of 0.5 mg/dl) RRT Started UO <.3ml/kg/h x 24 hr or Anuria x 12 hrs High Specificity

RIFLE max Cumulative Survival 1,0,8,6,4 Non ARD Risk Injury Failure,2 0,0 0 P<0.001 (Log Rank) 30 60 90 Days after hospital Length admission of hospital stay (d) Hoste et al. Crit Care. 2006;10(3):R73

Acute Interactions 100 80 % Mortality 60 40 20 0 Kidney K + 1 K + 2 K + 3 Number of failing organs

Prevalence/Incidence Estimates 2007 Any CVD: 80 million (1 in 3) Htn: 73 million CAD: 16 million AMI: 8.1 million CHF: 5.3 million Stroke: 5.8 million Congenital: 0.6-1.3 million 2007 Any 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 yr Approximately 20% to 40% of patients admitted to a hospital for acute heart failure have comorbid renal 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 ) AHA/ACC Circulation 2008

Inotropic Agents Dopamine Dobutamine Levoximendan Milrinone Enoximone Acute CRS To increase cardiac output in low output if proven or to maintain blood pressure Some inotropic agents may decrease peripheral resistances Arrhythmias; Receptor desensitization with prolonged use; Some may adversely affect outcome Vasopressors Epinephrine Norepinephrine Acute CRS Norepinephrine indicated only in cardiogenic shock when other inotropic therapies fail Epinephrine indicated only as rescue therapy for cardiac arrest, not as an inotrope

Vasodilators Nitroprusside Nitrates Acute CRS Indicated if organ congestion is present Increase renal and peripheral blood flow Hypotension especially in hypovolemic patients; Cyanide intoxication for nitroprusside Nesiritide Vasopressin Antagonists Acute CRS BNP analogue Vasodilator Data on mortality Uncertain Hypotension Can worsen kidney function, but data uncertain 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

Endothelin Antagonists Adenosine A1- receptor antagonists Chronic CRS and Chronic RCS Acute and chronic CRS Aimed to block endothelin II mediated vasoconstriction Block adenosine glomerular vasoconstriction May improve symptoms and prevent deterioration in renal function No changes in mortality Currently licensed only for Pulmonary hypertension with RV failure to improve EC 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

Morphine Acute CRS Relief of dyspnoea, chest pain, helps NIV Respiratory depression

Syndromes Type 1 Acute Cardiorenal Type 2 Chronic Cardiorenal Type 3 Acute Renocardiac Type 4 Chronic Renocardiac Type 5 Secondary Organ failure sequence Systemic Disease 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 dysfunction Diastolic dysfunction Chronic 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 arrythmia Troponin/ ST elevation ECHO: dilatation Decreased EF Increased CVP NYHF class 3-4 RIFLE R.I.F. or AKIN stage 1-2-3 or AKI requiring RRT CKD stage 1-5 or CKD requiring RRT APACHE 2 > SOFA SCORE > N. of failing organs Sequelae Inadequate renal perfusion Reduced diuretic responsiveness Worsening renal function Nephroangiosclerosis, chronic intesrt. Nephr. ADHF, severe arrythmias, shock LVH, Dilatative myocardiopathy, CHF ADHF - AKI Possible Criteria for sequelae RIFLE R,I,F by creatinine or urine output. CKD stage 1-5 Pulmonary edema, electrolyte imbalance arrythmias, cardiac arrest, reduced myocardiac contractility ADHF, AHF, pericarditis CHF Decreased EF Increased CVP NYHF 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, CRP Decreased GFR Serum Cystatine, Creatinine, NGAL. Urinary KIM-1, IL-18, NGAL, NAG Creatinine, Cystatic C, Urea, Uric Acid CRP Decreased GFR Creatinine, NGAL, IL-18, KIM-1, NAG

Conceptual Model for AKI Kidney Injury Continuum Vaidya VS, Ferguson MA, Bonventre JV. Biomarkers of Acute Kidney Injury. Annu Rev Pharmacol Toxicol 2008;48:463 493 Biomarkers (predictors) Biomarkers (prevention protection) Biomarkers (therapy)

Analyze Biology by Time Zones with Adequate and Precision Clocks Multiple Timezone Organ Damage Clock Display MOLECULAR CELLULAR BIOMARKER CLINICAL 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.