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Lettura: Nell’interpretazione della sindrome cardio-renale: quale è il ruolo della funzione renale dal punto di vista del cardiologo? Prof. Livio Dei Cas.

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Presentation on theme: "Lettura: Nell’interpretazione della sindrome cardio-renale: quale è il ruolo della funzione renale dal punto di vista del cardiologo? Prof. Livio Dei Cas."— Presentation transcript:

1 Lettura: Nell’interpretazione della sindrome cardio-renale: quale è il ruolo della funzione renale dal punto di vista del cardiologo? Prof. Livio Dei Cas Cattedra e U.O. di Cardiologia Dipartimento di Medicina Sperimentale ed Applicata Dipartimento Cardio-toracico Università e Spedali Civili di Brescia 9 th International Symposium Heart Failure & Co. Milano, Istituto Clinico Humanitas

2 Decreased cardiac performance Decreased cardiac output / increased venous pressure Impaired renal function ↓renal perfusion, ↑ renal venous pressure Increased water and Na + retention The Cardio-renal syndrome Hypertension Neurohormonal activation, inflammation, oxidative stress L Dei Cas, 1989

3 Cardio-renal syndrome: a definition Presence or development of renal dysfunction in patients with cardiac dysfunction –Chronic heart failure –Acute heart failure Patients are volume overloaded and/or with low cardiac output (dehydration must be excluded)

4 Cardio-renal syndrome Epidemiology Prognostic significance Mechanisms of renal damage Treatment

5 Cardio-renal syndrome Epidemiology Prognostic significance Mechanisms of renal damage Treatment

6 GFR, ml/min/1.73 m2 33% of patients with eCrCl <60 ml/min 60% of patients with eCrCl <60 ml/min Prevalence of cardio-renal syndrome Anavekar et al., New J Med 2004; 351:1285Heywood et al., J Card Fail 2007; 13:422

7 Gottlieb et al., J CardFail 2002; 8:136 Prevalence of worsening function in acute heart failure

8 Cardio-renal syndrome Epidemiology Prognostic significance Mechanisms of renal damage Treatment

9 Prognostic significance of cardio-renal syndrome Patient at risk of cardiovascular eventsPatient at risk of cardiovascular events Chronic heart failureChronic heart failure Acute heart failureAcute heart failure

10 Prognostic significance of cardio-renal syndrome Patient at risk of cardiovascular eventsPatient at risk of cardiovascular events Chronic heart failureChronic heart failure Acute heart failureAcute heart failure

11 Renal insufficiency: a cardiovascular risk factor? Results from the HOPE trial N = 980 with serum-creatinine 1.4 – 2.3 mg/dl N = 8,208 with serum-creatinine < 1.4 mg/dl Renal pts: older, more male, less diabetes, more CAD, higher SBP, more antihypertensives Mann, Gerstein, Yusuf, Ann Int Med, 2001;134:629-36

12 Renal insufficiency as a predictor of cardiovascular outcomes : the HOPE randomized trial Hazard ratio95% Conf. Interv. Creat >1.4mg/dl1.40(1.16 – 1.69) Microalbuminuria1.59(1.37 – 1.84) Coronary Art. Dis.1.51(1.22 – 1.85) Periph. Vasc. Dis.1.49 (1.29 – 1.70) Diabetes mellitus1.42(1.23 – 1.65) Male1.20(1.01 – 1.43) Age (1 year)1.03(1.02 – 1.05) Ramipril0.79(0.69 – 0.89) Mann et al., Ann Int. Med 2001, 134;629-36

13 Renal insufficiency as a predictor of cv outcomes and the impact of ramipril: the HOPE randomized trial Mann et al., Ann Intern Med 2001; 134:629

14 Renal insufficiency as a predictor of cv outcomes and the impact of ramipril: the HOPE randomized trial Mann et al., Ann Intern Med 2001; 134:629

15 Anavekar, N. S. et al. N Engl J Med 2004;351:1285-1295 Relation between Glomerular Filtration Rate and Outcome after Myocardial Infarction with LV Dysfunction and/or CHF and Serum Creatinine <2.5 mg/dl: VALIANT Trial All Cause Mortality CV Composite End Point

16 Hazard Ratio for Death From Any Cause, According to eGFR at Baseline 14 12 10 8 6 4 2 0 0204080 60 100120140 Estimated GFR (mL/min/1.73 m 2 ) Hazard ratio (95% CI) for death from any cause Anavekar NS, et al. N Engl J Med. 2004;351:1285-1295.

17 Prognostic significance of cardio-renal syndrome Patient at risk of cardiovascular eventsPatient at risk of cardiovascular events Chronic heart failureChronic heart failure Acute heart failureAcute heart failure

18 81% 72% 70% 86% Serum creatinine 0.0 0.2 0.4 0.6 0.8 1.0 061218243036 Months Fraction of patients Glomerular filtration rate 0.0 0.2 0.4 0.6 0.8 1.0 061218243036 Months Creatinine > 1.2 mg% (n=96) Creatinine < 1.2 mg% (n=99) P = 0.07 GFR > 70 ml/hr (n=100) GFR < 70 ml/hr (n=95) P = 0.003 Freedom from Death of the Patients Assessed Before Beta-blocker Treatment. Value of Renal Function Dei Cas et al., 2006

19 Proportional Relationship of eGFR With Mortality in Cox-Adjusted Survival Analysis: data from PRIME II 0.0 GFRc (mL/min)> 7659 – 7644 – 58 7659 – 7644 – 58< 44 LVEF (%)> 3026 – 3020 – 25 3026 – 3020 – 25< 20 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.01.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 02505007501,0001,250 Days > 76 mL/min 59 – 76 mL/min 44 – 58 mL/min < 44 mL/min Relative risk for mortality Proportion survival GFRc LVEF Hillege HL, et al. Circulation. 2000;102:203-210.

20 Survival by Baseline GFR in SOLVD (6630 patients) Al-Ahmad et al., JACC 2001; 38:955

21 Predictive value of renal dysfunction in CHF 6797 CHF subjects (NYHA III-IV) from SOLVD Trials Multivariate analysis of survival in subjects with baseline serum Cr 2.0 excluded) OutcomeRR95% CIP value All cause mortality1.411.25-1.59P<0.001 Pump failure death1.501.25-1.80P<0.001 Sudden death1.280.99-1.63P=0.051 Dries et al. J Am Coll Cardiol 2000; 35:681

22 CHARM Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure. Results from CHARM Low LVEF Preserved LVEF Hillege et al., Circulation. 2006;113:671-678

23 Prognostic significance of cardio-renal syndrome Patient at risk of cardiovascular eventsPatient at risk of cardiovascular events Chronic heart failureChronic heart failure Acute heart failureAcute heart failure

24 Serum Creatinine at Discharge and Outcome in patients discharged after an AHF Hospitalization P=0.008P=0.040 S-Creatinine ≤ 1.3 mg/dl S-Creatinine >1.3 mg/dl S-Creatinine ≤ 1.3 mg/dl S-Creatinine >1.3 mg/dl Dei Cas et al. in press

25 Variables Selected by Multivariable Analysis for the Prediction of Mortality HFSSEFFECTADHEREOPTIME-CHF Agevvv Heart ratevv SBPvvvv Resp. Ratev LBBBv LVEFv pVO2v BUNvvv s-Sodiumvvv CADv Comorbiditiesv NYHA classv

26 Prognostic significance of renal dysfunction in patients with acute HF: ADHERE registry Heywood et al. J Card Fail. 2007;13:422-30 N=118 465

27 ADHERE: Risk Stratification for Inhospital Mortality in the Validation Cohort 32,229 hospitalizations BUN < 43 mg/dL Mortality, 2.8% BUN ≥ 43 mg/dL Mortality, 8.3% 24,702 hospitalizations6,697 hospitalizations SBP ≥ 115 mmHg Low risk 2.3% mortality SBP < 115 mmHg Intermediate risk 5.7% mortality SBP ≥ 115 mmHg Intermediate risk 5.6% mortality SBP < 115 mmHg 15.3% mortality 1,862 hospitalizations S-creatinine < 2.75 mg/dL Intermediate risk 13.2% mortality S-creatinine ≥ 2.75 mg/dL High risk 19.8% mortality Fonarow GC, et al. JAMA. 2005;293:572-580.

28 Patients at risk Absolute and percent s-Cr change: Absolute s-Cr change: < 0.3 or 25%211143 92 5536< 0.3184125794633 ≥ 0.3 & 25%10764361914≥ 0.313482492721 HF hospitalizations and CV-mortality–free survival 55% 28% 0.0 0.2 0.4 0.6 0.8 1.0 090180270360450540630720 Days Patients (%) CV-mortality–free survival P < 0.001 Δ creatinine < 25% and/or < 0.3 mg/dL Δ creatinine ≥ 25% and ≥ 0.3 mg/dL 86% 59% 0.0 0.2 0.4 0.6 0.8 1.0 090180270360450540630720 Days Prognostic Significance of Worsening Renal Function in Patients With ADHF P < 0.001 Δ creatinine < 25% and/or < 0.3 mg/dL Δ creatinine ≥ 25% and ≥ 0.3 mg/dL Patients (%) Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.

29 Worsening Renal Function and outcome lower risk for WRF higher risk for WRF.1.2.5 1 2 4 8 Study Odds ratio (95% CI) Inhospital patients Krumholz (2000), n=1681 1.41 ( 1.10, 1.82) Smith (2003), n=412 1.73 ( 1.00, 2.98) Akhter (2004), n=480 2.62 ( 1.66, 4.13) Cowie (2006), n=299 Jose (2006), n=1854 Khan (2006), n=6535 Owan (2006), n=6052 Outhospital patients Subtotal De Silva (2005), n=1216 Subtotal Overall 1.44 ( 0.98, 2.09) 1.61 ( 1.35, 1.93) 1.71 ( 0.96, 3.05) 1.46 ( 1.06, 2.02) 1.49 ( 1.30, 1.71) 1.69 ( 1.48, 1.94) 1.79 ( 1.59, 2.02) 1.62 ( 1.45, 1.82) Damman et al. J Card Fail 2007

30 Why is renal dysfunction an independent prognostic factor in heart failure Need of higher diuretics doses Lower tolerance of life saving therapies (RAA inhibitors) Anemia Neurohormonal & inflammatory activation Oxidative stress, endothelial dysfunction ???...

31 Ahmed, A. et al. Eur Heart J 2006 27:1431-1439 Chronic diuretic use and increase in mortality: a retrospective analysis with propensity score methods from DIG trial All cause mortality Heart failure mortality

32 Ahmed, A. et al. Eur Heart J 2006 27:1431-1439 Chronic diuretic use and increase in hospitalisations: a retrospective analysis with propensity score methods from DIG trial All cause hospitalisations HF hospitalisations

33 Diuretic resistance predicts mortality in patients with advanced HF: PRAISE post-hoc analysis Neuberg et al., Am Heart J 2002; 144:31

34 Relation of Loop Diuretic Dose to Mortality in Advanced Heart Failure: a study on 1,354 patients Eshaghian … Fonarow, Am J Cardiol 2006; 97:1759,

35 Predictors of Worsening Renal Failure Among 318 Patients Hospitalized for AHF Results of Multivariable Analysis Predictor Odds ratio (95% CI) P History of chronic kidney disease 1.84 (1.04 – 3.27) < 0.0001 IV furosemide dose > 100 mg/d 2.18 (1.27 – 3.73) 0.004 NYHA class (IV vs. III) 2.07 (1.24 – 3.45) 0.005 LV ejection fraction < 30% 1.66 (1.01 – 2.75) 0.047 Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.

36 Relation of Loop Diuretic Dose to Mortality in Advanced Heart Failure: a study on 1,354 patients Eshaghian … Fonarow, Am J Cardiol 2006; 97:1759,

37 ESCAPE: High-Dose Loop Diuretics in HF Associated With Increased 6-Month Mortality N = 433 Maximum inhospital diuretic dose PredictedObserved0.500.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 0100200300400500600700 Mortality Hasselblad V, et al. Eur J Heart Fail. 2007;9:1064-1069.

38 Kittleson, M. et al. J Am Coll Cardiol 2003;41:2029-2035 Prognostic significance of intolerance to ACE inhibitors for Circulatory-Renal limitations (CRLimit) On ACEi, n=173 CR Limit, no inotropes, n=45 1.0 – 0.9 – 0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0.0 – I I I I I I I 0 2 4 6 8 10 12 14 16 18 20 22 24 26 149 120 90 66 46 32 31 10 30 22 16 127 5 3 1 CRLimit vs. on ACE: HR, 2.8 (1.8 to 4.4; p<0.0001) adjusted for age, SBP, creatinine… Months from hospitalization Event-free survival CR Limit, on inotropes, n=14 3 Inotropes vs. no inotropes: p=0.0002

39 Impact of congestive heart failure, chronic kidney disease, and anemia on survival in the Medicare population. An analysis of 1,136,201 patients Herzog et al. J Cardiac Fail 2004

40 COMET: Mortality and Anaemia Komajda et al., Eur Heart J. 2006 Jun;27(12):1440-6.

41 Hartog, J. W.L. et al. Eur Heart J 2007 28:2879-2885 Prognostic value of advanced glycation end- products in chronic heart failure

42 Cardio-renal syndrome Epidemiology Prognostic significance Mechanisms of renal damage Treatment

43 Pathophysiology of CRS: role of renal blood flow Ljungman et al. Drugs 1990;39 suppl 4:10-21 When Cardiac Index is reduced by 25%; RBF is decreased by 40% Cardiac Index (ml/min/m 2 ) 0,01,21,62,02,4 GFR (ml/min/1.73m 2 ) 0 20 40 60 80 100 120 140 Renal Blood Flow (ml/min/1.73m ) 0 100 200 300 400 500 Filtration Fraction (%) 0 15 20 25 30 35 RBF FF GFR 2

44 Damman, K. et al. J Am Coll Cardiol 2009;53:582-588 Increased Central Venous Pressure Is Associated With Impaired Renal Function in Patients With CV Disease: Curvilinear Relationship Between CVP and eGFR According to Different Cardiac Index Values P=0.0217 Solid line = cardiac index <2.5 l/min/m 2 ; dashed line = cardiac index 2.5 to 3.2 l/min/m 2 ; dotted line = cardiac index >3.2 l/min/m 2. Central venous pressure

45 Determinants of Glomerular filtration rate in patients with heart failure VariableUnivariate analysis Partial R P value Multivariate analysis Partial R P value Age-0.3380.001 Gender-0.3120.003 Renal blood flow0.888<0.0010.938<0.001 Filtration fraction0.573<0.0010.786<0.001 Urinary albumin excretion-0.3060.005 Mean BP0.3060.005 Hemoglobin0.3120.004-0.520<0.001 NT-proBNP-0.533<0.001 Plasma renin activity-0.501<0.001 sVCAM-1-0.2790.010 Nox-0.2760.011 ADMA-0.1680.126 CRP-0.0160.88 Damman et al. Clin Res Cardiol 2009; 98:121

46 Independent role of renal blood flow (RBF) and right atrial pressure (RAP) as determinants of Glomerular Filtration Rate in heart failure Multivariable regression analysis for GFR CI, cardiac index; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RBF, renal blood flow. VariableUnivariate correlation coefficient Univariate βMultivariate correlation coefficient Multivariate βMultivariate p-value Age− 0.072 0.023 Sex− 0.218− 0.028 RBF 0.797 0.797 0.782 0.782 0.664 0.664 0.621 0.621< 0.001 RAP− 0.616− 0.579 − 0.367 − 0.2760.020 CI 0.404 0.396 PVR− 0.298− 0.297 Adjusted R 2 0.609< 0.001 Damman et al. Eur J Heart Fail 2007;9:872-8.

47 Urinary neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage, and urinary Albumin Excretion (UAE) are increased in patients with chronic heart failure Damman et al., Eur J Heart Fail 10 (2008) 997–1000

48 Pathophysiology: Renal Blood Flow and Central Venous Pressure Damman et al. Eur J Heart Fail 2007;9:872-8.

49 Regulation of Intraglomerular Pressure

50 Role of Angiotensin II in the Pathogenesis of Renal Disease Ang II Efferent constriction PG, NO Afferent dilation Glomerular hypertension Proteinuria Focal segmental glomerulosclerosis Hypertension TGF-   Extracellular matrix Interstitial fibrosis PG = prostaglandin; NO = nitric oxide.

51 RENAAL: Baseline proteinuria as a determinant for cardiac events in T2DM De Zeeuw et al; Circulation 2004; 110: 921-27 CV EndpointHeart Failure 012243648 Month 0 20 40 60 % with CV endpoint ≥3.0g/24h <1.5 g/24h 012243648 Month 0 20 40 60 % with heart failure endpoint  3.0 g/24h <1.5 g/24h

52 High Prevalence of Microalbuminuria in Chronic Heart Failure Patients Van de Wall et al., J Card Fail 2005; 11:602

53 Neurohormonal markers in patients with heart failure with and without microalbuminuria Van de Wall et al., J Card Fail 2005; 11:602

54 Relation between Renal Blood Flow and Urinary Albumin Excretion in patients with Heart Failure Damman et al. Clin Res Cardiol 2009; 98:121

55 Cardio-renal interactions in heart failure Heart failure ↓renal blood flow ↓Glomerular filtration rate ↑diuretics Salt water retention ↑venous congestion Worsening renal function anemia Albuminuria

56 Pathophysiology of CRS: role of albumninuria Damman et al., 2009 Urinary Albumin Excretion raises exponentially with lower RBF

57 Pathophysiology: summary ↓ Renal blood flow Efferent vasoconstriction↑Glomerular pressure (microalbuminuria) Tubular damage ↑Central venous pressure Tubulo-glomerular feedback

58 Treatment and cardio-renal syndrome  Inotropic agents  Vasodilators  Vasopressin antagonists  Adenosine antagonists  Ultrafiltration  RAA inhibitors

59 Holmes CL, et al. Chest. 2003;123:1266-1275. A Meta-Analysis of the Use of Dopamine in Acute Renal Failure

60 Levosimendan Improves Renal Function in Patients With ACHF Awaiting HTx 1.92  1.60 Zemljic G, et al. J Card Fail. 2007;13:417-421. 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0Baseline 3 months Creatinine (mg/dL) Levosimendan 1.91  1.90 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0Baseline 3 months Creatinine (mg/dL) Controls

61 Risk of Worsening Renal Function with Nesiritide in Patients with ADHF A, nesiritide <0.03 μg/kg/min vs non-inotrope based controls; B, nesiritide <0.03 μg/kg/min vs all controls; nesiritide <0.015 μg/kg/min vs non-inotrope based controls; C,nesiritide <0.015 μg/kg/min vs non-inotrope based controls; D, nesiritide <0.015 μg/kg/min vs all controls; E, nesiritide <0.06 μg/kg/min vs non-inotrope based controls; F, nesiritide <0.06 μg/kg/min vs all controls 0 0.5 1 1.5 2 2.5 F E D C B A Risk ratio (95% CI) Nesiritide better Nesiritide worse Sackner-Bernstein et al., Circulation 2005; 111:1487

62 Sackner-Bernstein, J. D. et al. JAMA 2005;293:1900-1905. Mortality Within 30 Days of Treatment Associated With Nesiritide or Control Therapy

63 OutpatientInpatie nt EVEREST: Changes in Renal Function with Tolvaptan BUN (mg/dL) Serum Cr (mg/dL) After Discharge (wk)Inpatient

64 EVEREST: Tolvaptan in ADHF 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 24211815129630 Months in study Proportion surviving All-cause mortality Log-rank test: P = 0.76 Peto–Peto–Wilcoxon Test: P = 0.68 Stratified Peto–Peto–Wilcoxon Test: P = 0.68 Est. 1-year mortality, 25 vs. 26%; HR 0.98 Tolvaptan Placebo Konstam MA, et al. JAMA. 2007;297:1319-1331.

65 Elkayam, U. et al. J Am Coll Cardiol 1998;32:211-215 Doppler flow velocity signal measured in the renal artery at baseline and during adenosine infusion in one of the study patients

66 Elkayam, U. et al. J Am Coll Cardiol 1998;32:211-215 Effects of adenosine on renal haemodynamics Renal blood flow Renal vascular resistance

67 Change in Urine Volume and renal function with Furosemide and Adenosine antagonist (BG9719) 05001000150020002500 Urine output 0 – 8 hours (mL) Day 1 – Baseline Δ GFR 1 – 8 hours (%) Placebo Furosemide alone BG9719 + Furosemide BG9719 Gottlieb SS, et al. Circulation. 2002;105:1348-1353. −25 −20 −15 −10 −5−5 0 5 10 15 20

68 PROTECT Pilot 1 ° Endpoint: relief of dyspnea with no worsening heart failure or renal failure Placebo (n = 78) 10 mg (n = 74) 20 mg (n = 75) 30 mg (n = 74) Rolofylline Subjects (%) Failure Unchanged Success 0 10 20 30 40 50 60 70 80 90 100 3753 16 28 53 OR for failureRef 0.770.730.51 95% CIs0.43 –1.390.40 – 1.310.28 – 0.94 Cotter G, et al. J Card Fail. 2008;14:631-640.

69 PROTECT Pilot Change in Serum Creatinine −0.05 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 Day 2Day 3Day 7Day 14 Mean change in serum creatinine (mg/dL) Placebo (n = 78) 10 mg (n = 74) 20 mg (n = 75) 30 mg (n = 74) *Nominal P < 0.05 for dose-related trend at Day 14 Cotter G, et al. J Card Fail. 2008;14:631-640.

70 Ultrafiltration in Advanced HF Clinical benefits:  ↓ peripheral and pulmonary edema  ↓ PA pressures  ↓ neurohormonal activation  ↑ subsequent diuretic efficacy  Persistent effects for several months

71 UF n =7290694786717566 SC n =8491755290756762 Ultrafiltration vs. IV Diuretics in Patients Hospitalized for ADHF Dyspnea score 7 6 5 4 3 2 1 Ultrafiltration Standard care m = 6.4, CI ± 0.11 (n = 80) m = 6.1, CI ± 0.15 (n = 83) P = 0.35 Ultrafiltration Standard care Weight loss (kg) 6 5 4 3 2 1 0 m = 5.0, CI ± 0.68 kg (n = 83) m = 5.0, CI ± 0.68 kg (n = 83) m = 3.1, CI ± 0.75 kg (n = 84) P = 0.001 1° efficacy endpoints 1° safety end points P > 0.05 at all times Costanzo MR, et al. J Am Coll Cardiol. 2007;49:675-683.

72 Freedom From Heart Failure Rehospitalization in UNLOAD100 80 60 40 20 0 0102030 40 5060708090 Ultrafiltration arm (16 events) Standard care arm (28 events) P = 0.037 Number of patients at risk Ultrafiltration 88858077757270666445 Standard care 86837774666359585241 Patients free from rehospitalization (%) Days Costanzo MR, et al. J Am Coll Cardiol. 2007;49:675-683.

73 RENAAL: Losartan vs Placebo in type II diabetics with nephropathy: First Hospitalization for Heart Failure 012243648 Months 0 5 10 15 20 % with event Risk Reduction: 32% p=0.005 P (+CT) L (+CT) 76268561637553 75170163738874 P L Brenner BM et al New Engl J Med 2001;345(12):861-869.

74 Irbesartan Diabetic Nephropathy Trial (IDNT) Time to CHF Hospitalization (1,715 patients with hypertension, type 2 diabetes, and overt proteinuria) 0 0 6 6 12 18 24 30 36 42 48 54 Follow-up (months) 60 30 0 0 10 20 Irbesartan Amlodipine Placebo RRR 37% p < 0.001 RRR 23% p = 0.15 Subjects (%) Berl et al., Ann Intern Med. 2003;138:542-549.


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