European Society of Cardiology 2011 Paris-France Pathophysiology of Cardio-Renal Interactions Claudio Ronco, MD Department of Nephrology St. Bortolo Hospital International Renal Research Institute Vicenza - Italy
DECLARATION OF CONFLICT OF INTEREST Speaker honoraria from Abbott Alere Gambro
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 Interactions Basically a vicious circle Primary Insult Primary Insult ADHF - CHF AKI - CKD AKI-CKD Physiological derangements ADHF-CHF Physiological derangements Renal dysfunction Heart dysfunction
Acute ADHF leading to AKI Cardiac Surgery Cardiac procedures CIN CPB Valve replacement Cardio-Renal Chronic HF (systolic or diastolic) leading to : CKD CKD progression Diuretic resistant oliguria Chronic Acute Kidney Injury leading to AHF Volume/uremiainduced ADHF Renal ischemiainduced ADHF Sepsis/cytokine induced AKI and HF Reno-Cardiac CKD increasing cardiovascular mortality CKD increasing cardiovascular morbidity Chronic HF progression due to CKD Uremia related HF Volume related HF
Cardio-Renal syndromes General Definition: Pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction 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 and permanent 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, cardiac hypertrophy and/or increased risk of adverse cardiovascular events CRS Type V (Secondary Cardiorenal Syndrome) Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction
A widely accepted classification
CRS Type 1 CRS Type 2 AKI CKD Markers of Damage NGAL, Cystatin C, KIM 1 Markers of Function BUN, Creatinine, GFR/eGFR
Cardio-Renal Syndrome Type 1 Hemodynamically mediated damage Decreased CO Exogenous Factors Contrast media ACE inhibitors Diuretics Decreased perfusion Toxicity Vascocostriction. Increased venous pressure Acute Heart Disease Acute decompensation Ischemic insult Coronary angiography Cardiac surgery Humoral signalling BNP Sympathetic Activation Neuro-mediated damage RAA activation, Na + H2O retention, vasoconstriction Hormonal factors Immune mediated damage Natriuresis Cytokine secretion Acute Kidney Injury Renal hypoperfusion Reduced oxygen delivery Necrosis / apoptosis Decreased GFR Resistance to ANP/BNP Caspase activation Apoptosis Monocyte Activation Endothelial activation Caspase activation Apoptosis
Cardio-Renal Syndrome Type 1 LCOS and Congestion Acute Heart Disease Acute Kidney Injury Upon initial recognition, AKI induced by primary cardiac dysfunction implies inadequate renal perfusion until proven otherwise. This should prompt clinicians to consider the diagnosis of a low cardiac output state (LCOS) and/or marked increase in venous pressure leading to kidney congestion. It is important to remember that central venous pressure translated to the renal veins is a product of right heart function, blood volume, and venous capacitance which is largely regulated by neuro-hormonal systems. Specific regulatory and counter-regulatory mechanisms are activated with variable effects depending on the duration and the intensity of the insult.
RAA SYSTEM ANP - BNP SYMPATHETIC NS VASOPRESSIN
Cardio-Renal Syndrome Type 1 Hemodynamic mechanisms Vasocostriction Decreased cardiac output Arterial underfilling Functional (Pre-renal) Diseased heart Compensatory Mechanisms Decreased perfusion pressure A K I Increased preload Vasoconstriction Vasodilatation Parenchymal Venous congestion Increased venous pressure
Cardio-Renal Syndrome Type 1 Compensatory mechanisms in HF Natriuresis Afterload Vasocostriction Sympathetic Nervous System R-A-A System Arginin Vasopressin Endothelin Water excretion Sodium excretion Urea readsorption HF Compensatory Mechanisms Natriuresis Afterload Natriuretic Peptides Chinin-kallicrein System Prostaglandins Endothelial Relaxin Factor Vasodilatation Water excretion Sodium excretion Urea readsorption
AVP in normal and failing heart Normal Heart AVP Sympathetic tone decrease Vasodilat. RAA Water excretion Sodium excretion INCREASED ATRIAL PRESSURE BNP Non-osmotic AVP release Arterial underfilling V 1a -mediated vasocostriction AVP V 2 receptors RAA Water excretion Failing Heart BNP Sodium excretion Urea readsorption
Time windows for AKI management Fluids Drugs Nephroprotection? Diuretics RRT
RIFLE max and AKI outcomes 1,0,8,6,4 Non ARD Risk Injury Failure,2 0,0 0 P<0.001 (Log Rank) 30 60 90 Days after Length hospital of hospital admission stay (d) Hoste et al. Crit Care. 2006;10(3):R73
Biology of AKI by Time-Zones BIOMARKERS Multiple Timezone Organ Damage Clock Display MOLECULAR CELLULAR BIOMARKER CLINICAL
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 Hemodynamically mediated damage Decreased CO Decreased perfusion Increased venous pressure Acute Heart Disease Humoral signalling BNP Diuretics & UF Sympathetic Activation Humorally mediated damage RAA activation, Na + H2O retention, vasoconstriction Hormonal factors Immune mediated damage Toxicity Vascocostriction. Natriuresis Cytokine secretion Acute Kidney Injury Renal hypoperfusion Reduced oxygen delivery Necrosis / apoptosis Decreased GFR Resistance to ANP/BNP Caspase activation Apoptosis Monocyte Activation Endothelial activation Caspase activation Apoptosis
Time Course of worsening of renal function (Creatinine increase) in hospitalized HF patients Gotlieb et Al, JACC 2008 DIURETICS
Management with the Five B Balance & BW Blood Pressure Biomarkers Bioimpedance Blood Volume
2000 1500 Creatinine 1.8 1.6 1000 1.4 500 1.2 0 Day 0 Diuretics Day 1 Day2 Day 3 Day 4 Day 5 0.8 BNP Diuresis
2000 Stop Diuretics «5B» 1.8 1500 1000 NGAL Warning Creatinine 1.6 1.4 500 1.2 0 0.8 Day 0 Diuretics Day 1 Day2 Day 3 Day 4 Day 5 NGAL BNP Diuresis
Transcellular water flux Osmolality Interstitium Intravascular Refilling Starling Forces Cardiovascular Conditions Vascular Space Blood Volume Extracorporeal Uf
R e l a t i v e C h a n g e s Blood Pressure Blood Volume Uf / Refilling rate related hypotension a Overall ECFV related hypotension a 1 UF beginning UF end
THE PATHWAY FOR FLUID BALANCE The 5 B approach Blood Pressure Drugs & SCUF Blood Volume BIOMARKERS B.I.V.A. HEART KIDNEY Body Weight - BALANCE
Cardio-Renal Syndrome Type 1 Hemodynamically mediated damage Decreased CO Decreased perfusion Increased venous pressure Acute Heart Disease Humoral signalling BNP Exogenous factors Contrast media ACE inhibitors Diuretics Sympathetic Activation Humorally mediated damage RAA activation, Na + H2O retention, vasoconstriction Hormonal factors Immuno mediated damage Toxicity Vascocostriction. Natriuresis Cytokine secretion Acute Kidney Injury Renal hypoperfusion Reduced oxygen delivery Necrosis / apoptosis Decreased GFR Resistance to ANP/BNP Caspase activation Apoptosis Monocyte Activation Endothelial activation Caspase activation Apoptosis INFLAMMATION
Current issues in AKI management
APOPTOSIS STUDY IN CRS Type 1 Patient Table 1. Baseline characteristics of CRS Type 1 patients and clinical parameters Sex Age (years) CKD Stage Cause of CKD Creatinine at enrollment (mg/dl) Urea at enrollment (mg/dl) AKI N stage at enrol lmen t RRT Prior MI or revascularization Prior history of cardiac disease 1 M 83 V Uncertain 4.9 150 1 Yes Yes ICM 2 M 80 III DM 1.7 208 1 No No AF 3 M 71 V DM 5.4 293 3 Yes No No 4 M 28 V HTN 7.3 270 3 No No No 5 M 81 II DM 9.5 204 3 Yes No No 6 M 71 III DM 2.5 112 1 Yes No ICM 7 M 85 IV Uncertain 7.8 195 3 Yes No No 8 F 60 IV HTN 4.2 254 3 No No AF 9 M 85 V Uncertain 5.9 120 3 Yes Yes ICM 10 M 48 IV DM 4.8 211 3 Yes No AF 11 F 84 III DM 2.1 244 1 No No No 12 M 67 IV DM 4.1 318 3 Yes Yes ICM 13 F 82 IV Uncertain 7.6 107 3 Yes Yes ICM, HTN HD 14 F 80 IV HTN 2.0 95 1 No No DCM 15 M 88 III DM 2.4 233 1 No Yes ICM
APOPTOSIS STUDY IN CRS T.1 and CONTROLS Plasma-induced apoptosis after 72h (%) Plasma-induced apoptosis after 96h (%) CRS Type 1 patients Healthy controls (n=15) (n=20) p-value 78 (52.0 to 93.0) 11 (10.0 to 12.5) <0.001 81 (62.0 to 92.0) 11 (10.5 to 13.0) <0.001 Caspase-8 (S/B ratio) 0.91 (0.75 to 1.02) 0.44 (0.41 to 0.52) 0.01 Evaluation of apoptosis and Caspase-8 activity in U937 cells after incubation with plasma from CRS Type 1 patients and healthy volunteers. Results (median, interquartile range) are given as percentage of apoptotic cells/field for apoptosis at 72h and 96h or signal to background (S/B) ratio for Caspase-8 activity at 24h
Percentage of Apoptosis APOPTOSIS STUDY IN CRS T.1 and CONTROLS Evaluation of percentage of apoptosis in U937 cells after incubation with plasma from CRS Type 1 patients and healthy volunteers for 72h and 96h 120 78 81 100 80 60 40 20 11 11 0 CTR 72h CRS Type1 72h CTR 96h CRS Type1 96h
Cardio-Renal Syndrome Type 1 Inflammation/humoral theory Cytokines Supernatant R T C Colture Plasma Monocyte Cell Colture Apoptosis Apoptosis
APOPTOSIS STUDY IN HEART FAILURE 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 100,0% 80,0% p=0.008 p=0.006 p=0.006 p=0.05 60,0% 47,6% 51,4% 47,0% 58,8% 40,0% 28,0% 30,8% 36,8% 20,0% 16,5% 0,0% 24h 48h 72h 96h HF/No AKI HF/AKI n.6 n.6
Cardiorenal Syndrome Patient Subsets Low EF High CVP Low CO/CI Poor perfusion Poor Renal Perfusion 20% Fixed CKD 20% egfr < 60 DM HTN Intercurrent event/procedure Neurohumoral Decomp 60% Baseline egfr ~75 ml/min Set off by IV diuresis ( RAAS, SNS) Initially BP Other drug insults (Na, NSAIDS, TZD s, others) Intercurrent event/procedure McCullough, ACC 2006
Cardiorenal Syndrome Patient Subsets De Novo HF 15% 25% ACS and cardiogenic shock 60% ADHF on Established HF ADQI,2008
Cardio-Renal Syndrome Type 1 Acute Heart Disease Acute Kidney Injury Occurs in ~25% of unselected patients admitted with ADHF. Among these patients, pre-morbid CKD is common and predisposes to AKI in approximately 60% of cases. AKI is an independent risk factor for 1-year mortality in ADHF patients including in patients with ST-elevation myocardial infarction who develop signs and symptoms of heart failure or have a reduced left ventricular ejection fraction. This independent effect might be due to an associated acceleration in cardiovascular pathobiology due to kidney dysfunction through the activation of neurohormonal, cell signaling, oxidative stress, or exuberated repair (fibrosis) pathways.
Cardio-Renal Syndrome: possible pathophysiological mechanisms of AKI following HF Hemodynamic deterioration (congestion, CO, perfusion) Myocardial damage injury HF progression Renal dysfunction (AKI) Neurohormonal & cytokine activation Gheorghiade M et al. Am J Cardiol. 2005
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 N=1,681 Krumholz HM et al. Am J Cardiol. 2000;85:1110.
Obesity and cardiometabolic changes Diabetes Sleep Apnea Heart Disease G.I. Tract Disorders Obesity Kidney Disease High Blood Pressure TNF-a IL-6 F F A Inflammation CRP Atherosclerosis Coronary artery disease Cardiac remodelling LVH-Dilatation Lean adipose tissue Obese adipose tissue Crosstalk Leptin Resistin Adiponectin Apoptosis Dysmetabolic syndrome Chronic ischemia CKD Fibrosissclerosis
CARDIO-RENAL CACHEXIA SYNDROMES Non-oedematous weight loss of >6% of total body weight over a period of 6 or more months CRS TYPES 1-2 CRS TYPES 3-4 Low Cardiac output Na and fluid overload Chronic hypoperfusion Embolism Venous Congestion Chronic inflammation Cardiac Remodeling Endothelial Dysfunction Acceler. Atherosclerosis Na and fluid overload Chronic inflammation Uremic Toxins Malnutrition Anemia EPO resistance ph abnormalities Ca-P abmormalities Lack of VDR activation Soft Tissue calcifications Malnutrition, loss of >10% of lean tissue or percent of ideal weight <90%. CKD Progression, Apoptosis Necrosis, Fibrosis, Sclerosis Heart Failure, Systolic/diastolic dysfunction, Myoc.Remodelling
AKI Cardio-Renal Syndrome Anemia and Iron deficiency Reduced Blood Viscosity Decreased Oxygen Delivery Increased Sympathetic Activity Hyperdynamic circulation CKD Cardiac Work Cardiac Output Arterial diameter and volume Arterial wall tension Left ventricle hypertrophy Left Ventricle wall tension Eccentric remodelling of the arterial system AKI CKD Left ventricle eccentric remodelling
Cardio-Renal Syndrome CKD and UREMIA CKD + HD CVR CKD = CVR b * f ( + X) HD techno/dr
Cardio-Renal Syndrome CKD and UREMIA CKD Glomerular- -interstitial damage Sclerosis - Fibrosis Acquired Risk factors Primary nephropathy Anemia Uremic toxins Ca/P abnormalities Nutritional status, BMI Na H 2 O overload Chronic Inflammation Anemia & malnutrition Ca/P abnormalities Na H 2 O overload Unfriendly milieu Inflammation CHF
Cardio-Renal Syndrome The unfriendly uremic milieu Uremia retention products Bone remodeling Insulin resistance Muscle catabolism Acute phase reactants Fetuin-A Adipocytokine production Appetite REE Endothelial dysfunction Monocyte adhesion Smooth muscle cell proliferation LDL oxidation Vascular calcification Oxidant stress
Risk of Cardiorenal Syndrome (%) Risk of Cardiorenal Syndrome by Number of Risk Factors 6,0 5,0 4,0 3,0 2,0 1,0 16% 24% 29% 38% 53% 0,0 1 2 3 4 5 No. of Risk Factors Krumholz HM et al. Am J Cardiol. 2000;85:1110.
CONCLUSIONS Heart-kidney interactions are bidirectional, time-dependent, and the are mediated by several pathophysiological mechanisms PHYSICAL CHEMICAL BIOLOGICAL Pre existing or concomitant pathological conditions represent important risk factors for developing CRS
CONCLUSIONS Recognize patient subsets and risk factors Consider biomarkers for early identification Understand precipitating factors Medications Procedures Explore new avenues for CRS prevention and organ protection based on pathophysiological mechanisms