Pathophysiology of Cardio-Renal Interactions

Transcription

1 Pathophysiology of Cardio-Renal Interactions Claudio Ronco, MD Department of Nephrology St. Bortolo Hospital International Renal Research Institute Vicenza - Italy

2 Pathophysiology of Cardio-Renal Interactions Heart-Kidney Interactions: Bidirectional Temporally regulated (Acute and Chronic) Mediated by different mechanisms Different outcomes in specific populations Functional vs structural organ damage

3 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

4 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

5 Heart-Kidney Scenarios 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 Cardiovascular morbidity and mortality increased by end stage renal disease (ESRD) Chronic HF progression due to kidney dysfunction Uremia related HF Volume related HF Acute HF due to acute kidney dysfunction Volume/uremia-induced AHF

6 A widely accepted classification

7 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

8 CRS Type 1 CRS Type 2 AKI CKD Markers of Damage NGAL, Cystatin C, KIM 1 Markers of Function BUN, Creatinine, GFR/eGFR

9 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

10 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.

11 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

12 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

13 RAA SYSTEM ANP - BNP SYMPATHETIC NS VASOPRESSIN

14 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

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16 OVERHYDRATION

17 Time windows for AKI management Fluids Drugs Nephroprotection? Diuretics RRT

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

19 Increase in All-Cause Mortality with worse RIFLE Class Failure vs NonAKI Injury vs NonAKI Risk vs NonAKI N=71,527 patients Relative Risk

20 Biology of AKI by Time-Zones BIOMARKERS Multiple Timezone Organ Damage Clock Display MOLECULAR CELLULAR BIOMARKER CLINICAL

21 Clinical Continuum of AKI Devarajan, Biomarkers Med 4:265-80, 2010

22 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

23 AKI Biomarkers McIlroy et al, Anesthesiology 2010; 112:

24 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

25 Time Course of worsening of renal function (Creatinine increase) in hospitalized HF patients Gotlieb et Al, JACC 2008 DIURETICS

26 Management with the Five B Balance & BW Blood Pressure Biomarkers Bioimpedance Blood Volume

27 Creatinine Day 0 Diuretics Day 1 Day2 Day 3 Day 4 Day BNP Diuresis

28 2000 Stop Diuretics «5B» NGAL Warning Creatinine Day 0 Diuretics Day 1 Day2 Day 3 Day 4 Day 5 NGAL BNP Diuresis

29 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

30 Current issues in AKI management

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32 Cardio-Renal Syndrome Type 1 Inflammation/humoral theory Cytokines Supernatant R T C Colture Plasma Monocyte Cell Colture Apoptosis Apoptosis

33 APOPTOSIS STUDY IN CRS T.1 and CONTROLS Plasma-induced apoptosis after 72h (%) Plasma-induced apoptosis after 96h (%) CRS Type 1 patients Controls (HF no CRS) (n=15) (n=20) p-value 78 (52.0 to 93.0) 11 (10.0 to 12.5) < (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

34 Percentage of Apoptosis APOPTOSIS STUDY IN CRS T.1 and CONTROLS Evaluation of percentage of apoptosis in Monocytic cells after incubation with plasma from CRS Type 1 patients and Controls CTR 72h CRS Type1 72h CTR 96h CRS Type1 96h

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36 RTC APOPTOSIS STUDY IN CRS T.1 Evaluation of percentage of apoptosis in RTC cells after incubation with supernatant from Monocytes incubated 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% 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

37 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

38 CARDIORENAL SYNDROME: TYPE 2 Anemia Sodium and H2O retention Uremic solute retention Ca and P abnormalities Hypertension Increased susceptibility to insults Chronic Heart Disease Anemia, hypoxia RAA and sympathetic activation Na and H 2 O retention Ca and P abnormalities Hypertension, LVH Anemia Sodium and H 2 O retention Uremic solute retention Ca and P abnormalities Hypertension Genetic risk factors Acquired Risk factors Low cardiac output (CO) Low cardiac output (CO) Subclinical inflammation Endothelial dysfunction Accelerated atherosclerosis Chronic hypoperfusion Increased renal vascular resistance Increased venous pressure Embolism Chronic hypoperfusion Apoptosis Insult and Initiation of kidney damage Sclerosis - Fibrosis Progression of CKD

39 CARDIORENAL SYNDROME: TYPE 3 Decreased 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 Caspase activation Apoptosis Humoral Signalling Electrolyte, acid-base & coagulation imbalances Monocyte Activation Endothelial activation Cytokine secretion Caspase activation Apoptosis Acute decompensation Acute heart failure Ischemic insult Arrythmias Decreased CO BIOMARKERS Troponin Myoglobin MPO BNP

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

41 CARDIORENAL 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 oxidative stress toxemia Exogenous toxins heme proteins antibiotics, contrast media Organ damage/dysfunction LPS / endotoxin Monocyte activation cytokines Renal Insufficiency

42 Cardiorenal Syndrome Risk Factors Characteristics Adjusted OR 95% CI P Value Women 1.41 ( ).003 HTN 1.64 ( ).003 Rales>Bases 1.28 ( ).03 HR >100 bpm 1.34 ( ).01 SCr 1.5 mg/dl 1.77 ( ) <.001 SBP >200 mm Hg 1.63 ( ).009 N=1,681 Krumholz HM et al. Am J Cardiol. 2000;85:1110.

43 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, No. of Risk Factors Krumholz HM et al. Am J Cardiol. 2000;85:1110.

44 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

45 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

46 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

47 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

48 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

49 Cardio-Renal Syndrome CKD and UREMIA CKD + HD CVR CKD = CVR b * f ( + X) HD techno/dr

50 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

51 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