Understanding the Cardio-Renal Syndromes

Transcription

1 Understanding the Cardio-Renal Syndromes The Cardio-Renal axis: an underestimated player in cardiovascular diseases ESC Congress Munich 27/08/2012 Alberto Palazzuoli Department of Internal Medicine Cardiology Unit S. Maria alle Scotte Hospital, University of Siena Italy

2 Heart and Kidney: Dangerous liaison Regulation of volume and BP (Na + and H 2 O) Electrolyte and acid-base balance Hormonal function (Erythropoiesis Vascular tone) Blood purification from metabolic waste products Regulation of perfusion pressure and flow to periphery Electrical activity depend on electrolytes and acid-base Contractility depend on O 2, volume, electrolytes, toxin Hormonal function (ANP - BNP) ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

3 The Cardio-Renal Syndrome (CRS) How can we define it? Is an early diagnosis of AKI important? What is the exact significance of WRF? What is the link between heart and kidney? What is the prevalent pathophysiological mechanism?? ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

4 Common Characteristics of the Cardiorenal Syndrome Heart Reduced renal blood flow and GFR Increased venous congestio n Increased vascular resistance RAAS activity Diuretic resistance Albuminuri a Increased BUN Fluid overload Tubular and glomerula r damage Inflammato ry activation, endothelial dysfunction Anemia Kidney Palazzuoli, Ronco Heart Fail Rev 2011

5 Cardio Renal Syndromes acute Cardio-Renal Reno-Cardiac chronic Secondary Cardio-Renal Ronco, C. et al. J Am Coll Cardiol 2008

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7 The cardiorenal syndrome in heart failure Damman K et al. Prog Cardiovas Dis. 2011

8 When the Creatinine Rises Patient can t go home Diuretic doses are often decreased RAAS inhibitors are often discontinued Other medications are renally dosed Inotropes may be initiated PA catheter may be placed Foley catheter may be placed Renal advise may be ordered (and is rarely helpful)

9 Eventi/ 1000 persone/ anno Eventi/ 1000 persone/ anno Primary Outcome Myocardial Infarct Cardiovascular Death in pz. with creatinine <1.4 mg/dl or 1.4 mg/dl Eventi/ 1000 persone/ anno Eventi/ 1000 persone/ anno 80 Primary outcome Myocardial infarction All patients Placebo 0 Creatinine < 1.4 mg/dl Creatinine 1.4 mg/dl 0 Creatinine <1.4 mg/dl Creatinine 1.4 mg/dl Ramipril 40 Cardiovascular death 60 All death Creatinine <1.4 mg/dl Creatinine 1.4 mg/dl 0 Creatinine <1.4 mg/dl Creatinine 1.4 mg/dl HOPE Trial, Ann Intern Med, 2001

10 Demographic and Baseline Characteristics by Kidney Function Stage in ADHERE Database Parameter I (n=10,660) Kidney Function Stage II (n=32,433) III (n=51,533) IV (n=15,553) V (n=82769) p Age, mesn (SD), y ) 70.1 (14.7) 75.7 (12.0) 76.3 (11.6) 67.4 (14.7) <.0001 Atrial fibrillation <.0001 Diabetes <.0001 Hypertension <.0001 Peripheral vascular disease <.0001 Renal insufficiency <.0001 BNP, pg/ml, n ,243 22, ns Hb, means (SD), g/dl 13.0 (2.6) 13.0 (2.5) 12.3 (2.5) 11.4 (2.3) 11.5 (2.5) <.0001 Accross stage using chi-square tests for categoric variables and analysis of variance for continuos variables Heywood JT et al, J Card Fail, 2007

11 Main Clinical Outcomes by egfr Quartiles: OPTIME-HF Quartile 1 (n=234) Quartile 2 (n=235) Quartile 3 (n=234) Quartile 4 (n=234) egfr, ml min m (75-94) 60 (55-65) 45 (42-48) 29 (25-33) <0.01 Primary end point, d 5 (4-10) 6 (4-13) 7 (4-14) 8 (5-17) <0.01 Deaths, n(%) In hospital * 1 (0.44) 3 (1.3) 8(3.4) 16 (6.8) <0.01 At 60 days 10 (4.3) 9 (3.9) 25 (10.8) 44 (19) <0.01 Hazards ratio (95% CI) Referent 0.9 ( ) 2.63 ( ) 4.73 ( ) Readmissions/death within 60 days, n (%) 53 (22.9) 71 (31) 93 (40.1) 106 (45.3) <0.01 Odds ratio (95% CI) Referent 1.51 (1-2.29) 2.25 ( ) 2.8 ( ) P *Odds ratios for in-hospital death are questionable because of the small numbers of events and thus are not presented Raw percentages of patients followed up to the 60-day visit. Cox proportional-hazards regression using indicator variables was used to analyze 60- day death rate. Categorical variables were analyzed with logistic regression. Probability values represent overall relationship with egfr as a continuous variable for regression models. All individual quartiles vs lowest quartile, p<0.05 Klein M et al, Circ Heart Fail, 2008

12 Relationship Between Renal Parameters and 6-Months Outcomes Time to Death Time to Death or Rehospitalization HR* 95% CI P Value HR* 95% CI p Value Baseline SCr < < Baseline egfr < < Discharge SCr < < Discharge egfr < > 0.3 mg/dl SCr > 25% 2 egfr *Hazard ratio (HR) calculated per 0.3-mg/dl increments in serum creatinine (SCr) and per 10-ml/min decrements in estimated glomerular filtration rate (egfr). Worsening renal function, defined as: 1) an increase in SCr 0.3 mg/dl; and 2) a decrease in egfr 25% from baseline to discharge, is treated as a dichotomous variable. CI confidence interval. Nohria et al ESCAPE Trial JACC 2008

13 % Events Kaplan-Meier curves for CV mortality/morbidity stratified by egfr: SAVE study 60% 50% 40% 30% 20% 10% 0% egfr <60, placebo egfr <60, captopril egfr >60, placebo egfr >60, captopril 1 year 2 year 3 year 4 year Years post-mi Tokmakova et al SAVE Study Circulation 2008

14 cumulative incidence cumulative incidence Kaplan-Meier plot of cumulative incidence of cardiovascular death or unplanned admission to hospital for the management of worsening CHF in patients with reduced LVEF and preserved LV systolic function < > years < > years Hillege et al CHARM Circulation 2006

15 What is the real Risk when IR is associated to CHF % HR 1.56 (p= 0.001) Any impairment 51 HR 2.31 (p= 0.001) Moderate/severe impairment 24 No impairment Mortality: 15% for every 0.5 mg/dl increase in creatinine 7% for every 10 ml/min decrease in egfr Smith GL et al, J Am Coll Cardiol 2006

16 Cumulative survival (death or HF admission) WRF outcome during hispitalization and at early and post discharge: COACH study 1.0 WRF in-hospital WRF 0-6 months WRF 6-12 months No WRF WRF Follow-up time (days) Damman K et al. Eur J Heart Fail 2009

17 Clinical Characteristics and Outcomes of Patients With Improvement in Renal Function During the Treatment of Decompensated Heart Failure Testani JM et al. Journal of Cardiac Fail 2011

18 Potential mechanisms of increased mortality in WRF Marker of more decompensated HF Relationship due to cardio-renal interaction Discontinuation of common treatments Greater prevalence of coexistent diseases

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20 The traditional concept of WRF in acute HF Decrease in cardiac output Arterial underfilling Systemic and Renal vasocostriction Decreased perfusion pressure Increased neuro-hormonal activity Glomerular and interstitial damage

21 Acute CRS Type 1 Hemodynamically mediated damage Acute Heart Disease or Procedures Acute decompensation Ischemic insult Coronary angiography Cardiac surgery Caspase activation Apoptosis Decreased CO Humoral signalling BNP Exogenous factors Contrast media ACE inhibitors Diuretics Sympathetic Activation Humorally mediated damage RAA activation, Na + H2O retention, vasoconstriction Hormonal factors Immune mediated damage Monocyte Activation Endothelial activation Decreased perfusion Toxicity Vascocostriction. Natriuresis Increased venous pressure Cytokine secretion Caspase activation Apoptosis Renal hypoperfusion Reduced oxygen delivery Necrosis / apoptosis Decreased GFR Resistance to ANP/BNP BIOMARKERS KIM-1 Cystatin-C N-GAL Creatinine Acute Kidney Injury ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

22 Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes Characteristics overall cohort no SBP-reduction yes SBP-reduction P Demographics Age (years) 56.4± ± ± Males 74,1% 74,1% 74,1% Functional status/ ejection fraction NYHA class (mean class) 3.9± ± ± Six minut walk (feet) 422± ± ± MVO2 (ml/kg/min) 10.1± ± ± Ejection fraction 19.5± ± ± Systolic blood pressure 101.5± ± ±11.7 <0.001* Admission to discharge change in blood pressure Absolute 4.3± ± ±11.5 <0.001* Relative 2.8± ± ±8.2 <0.001* Laboratory findings GFR(mL/min/1.73 m 2 ) 56.9± ± ± * *Significant P- value. Testani et al. Eur J of Heart Fail 2011

23 Influence of renal dysfunction phenotype on mortality in the setting of cardiac dysfunction: analysis of three randomized controlled trials * LBC Low BUN creatinine HBC High BUN creatinine Testani JM et al. Eur J Heart Fail 2011

24 Blood urea nitrogen as biomarker of neurohormonal activation Kazory A Am J Cardiol 2010

25 Relationship Between Neurohormones and LVEF and GFR c GFR c LVEF Univariate r Multivariate Univariate Multivariate Norepinephrine 0.28 < NS Epinephrine NS Dopamine 0.23 < NS Renin <0.001 NS Aldosterone NS ANP 0.35 <0.001 < < N-terminal ANP 0.53 <0.001 < <0.001 <0.001 Endothelin NS Epinine NS NS Hillege HL et al. Circulation 2000

26 Adaptive response to renal hypoperfusion in HF Ruggenenti P et al. Eur H J 2011

27 VENOUS CONGESTION AND WORSENING RENAL FUNCTION Mullens et al, JACC, 2009

28 Relation among renal dysfunction and Congestion in CHF Damman K et al Eur J Heart Fail 2010

29 Is WRF as ominous prognostic sign in AHF patients? The role of congestion Variable Death, Transplant, or HF Rehospitalization Univariable HR (95% CI) * Univariable P Value Multivariable HR (95% CI) * Multivariable P Value Previous HF , CKD 1.69 < Laboratory characteristics Plasma hemoglobin, 0.59 < Serum sodium, admission 0.6 < Serum sodium, discharge Congestion and WRF. 1: Yes WRF and yes congestion 5.35 < (0.88, 2.2) : No WRF and yes congestion : Yes WRF and no congestion Reference: No WRF and no congestion Ref Ref Metra et al Circ Heart Fail 2012

30 Changes in renal parameters and Intra abdominal pressure Mullens W et al J Am Coll Cardiol 2008

31 Changes in IAP and serum creatinine in patients underwent to paracentesis or ultrafiltration Mullens W et al J Cardiac Fail 2008

32 Fluid overload: redistribution and accumulation mechanisms Increased vascular resistance Increased arterial stiffness leads to hightened afterload Fluid overload redistribution Increased venous return and preload Reduced capacitance in veins Cotter G et al Eur J Heart Fail 2008

33 Interaction among fluid overload cardiac output and mean blood pressure Haemodinamic control (Guyton) Volume expansion Increased cardiac output Total body autoregolation Increased peripheral resistance Increased blood pressure Pressure natriuresis Renal failure Cardiorenal connection NO-ROS Dysbalance Sympathetic Nervous Systolic Activation Renin Angiotensin System Activation Inflammation Heart failure Cardiovascular damage Bongartz L G et al. Eur Heart J 2005

34 Cardiac output Pulmonary hypertension RV failure Peripheral vascular resistance Venous congestion Arterial Underfilling Renal venous pressure Intra-abdominal pressure Neurohormonal Activation Renal interstitial pressure SNS activity RAAS activity AVP release? Myocardial depressant factor Renal hemodinamics and renal salt/water excretion Tang WW et al. Heart 2010

35 The The Perfect Storm Sorm

36 ADQI Creatinine Criteria Urine Output Criteria ADQI Risk Increased creatinine x1.5 or Creatinine increase > 0.3 mg/dl UO <0.5 ml/kg/h x 6 hr High Sensitivity Injury Creatinine increase x 2 UO <0.5 ml/kg/h x 12 hr Failure Creatinine increase x 3 or creatinine 4 mg/dl (Acute rise of 0.5 mg/dll UO <0.3 ml/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 ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

37 Mortality by RIFLE Class Mortality Non-AKI Risk Injury Failure 13 studies, n >71,000 patients ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

38 Acute Reno-Cardiac syndome: epidemiology Heterogeneity of AKI different methods to define AKI different risk profile in the enrolled population few studies reporting cardiac events clinical information about cardiac conditions at baseline POOR CLINICAL CHARACTERIZATION AND DEFINITION Cruz D et al Heart Fail Rev 2011

39 Causes of Acute Kidney Injury Preexisting renal insufficiency Glomerulonephritis Rhabdomyolysis Red. effective arterial volume Exogenous toxins Red. extracellular volume Cardio-Renal Impaired renal microcirculation Drug toxicity SIRS / sepsis ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

40 Neurormonal increase leads to Diuretic-Resistance Glomerul Norepinephrine (and endothelin) reduce blood flow and GRF Proximal Tubul Ang II increases Na resorbtion Collector Duct Aldosteron increases Na resorbtion Krämer et al. Am J Med. 1999;106:90.

41 Acute RCS 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 ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

42 DEGREES OF RENAL AND CARDIOVASCULAR DISEASES Renal terminal insufficiency Insuff. Renal Chronic ( FG) End Stage Progression Refractory heart failure Cardiovascular Events Age, obesity Diabetes hypertension Renal Disease Albuminuria Proteinuria Starting At risk LV Insufficiency Age, obesity Diabetes hypertension Cardiovascular Disease Sarnak MJet al, Am J Kidney Dis, 2000

43 Common factors for heart and kidney diseases Ronco C et al JACC 2012 (in press)

44 Parenchimal disease Treatment for HF Artery disease Renal dysfunction Neuroendocrine and cytokine activation Congestion and hypoperfus. Cleland JG et al Heart Fail Rev 2012

45 RAAS Effects In Renal and Cardiac diseases Renal effects sodium and water reabsrobtion Efferent arterioles constriction proteinuria increase glomerular sclerosis and tubular fibrosis Reduced medullary blood flow blood flow redistribution idrostatic and oncotic pressure Cardiovascular effects vascular muscle cell proliferation and thickness Increase blood pressure Left ventricular hypertrophy and fibrosis Increase atherosclerosis activity neuro hormonal overdrive impairment endothelial function Decrease fibrinolitic acitivity with plateled aggregation

46 Inflammatory activation: cardiac and renal interaction Inflammation Arteries and Veins Endothelial dysf & vascular stiffness Myocardium Contractility fibrosis & apoptosis Kidney Na retention & fluid intake Tubulo glomerular damage Congestion Colombo P et al Heart Fail Rev 2012

47 The role of Inflammation in Cardio-Renal syndrome Endothelial cells activation DAMP signaling Complement activation Leukocite infiltration Inflammation Platelet activation increase prthrombotic and Pro coagulative processes Capillary obstruction Peristent ischemia Rosner MH et al. Semin Nephrol 2012

48 Tubular damage in chronic systolic heart failure is Relationship between CKD and urinary NAG, NGAL and KIM-1. associated with reduced survival independent of glomerular filtration rate. Damman K et al. Heart 2010

49 Clinical outcome of renal tubular damage in CHF Adjusted for age, gender, egfr, and UACR Multivariable adjusted a Variable Multivariable HR P-value P CR Multivariable HR P-value P CR lognag (per SD) Mortality HF hospitalizations 1.38 ( ) 1.22 ( ) ( ) ( ) logkim-1 (per SD) Mortality HF hospitalizations 1.17 ( ) 1.13 ( ) ( ) ( ) logngal (per SD) Mortality HF hospitalizations 1.24 ( ) 1.01 ( ) ( ) ( ) 0.85 Damman K et al. Eur H J 2011

50 CONCLUSIONS The cardiorenal syndrome is heterogeneous group of pathophysiological entities and the clinical course depends on the prevalent mechanism by which the renal function is impaired There is priority to better understand the patophysiologic link between Heart and Kidney, and to know the more sensitive and specific parameters able to identify primitive organ damage their mechanism and significance WRF is a mirror of different clinical situation and it should be evaluated taking into account previous cardio-renal damages as well as hemodynamic and non hemodynamic conditions Pathophysiologic processes are different in CRS subtypes and involve several actors (hemodynamic, neurohormones, inflammation, fluid overload) We need to focus on research agenda designed to recognize the vicious circle of pathological heart-kidney interactions and mechanisms in every clinical condition Better assessment of congestion, fluid redistribution, neuro-endocrine overdrive, tubular and glomerular damage, could improve our understanding in CRS

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