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1 Worsening Renal Function in Heart Failure Patients Mark Drazner, MD, MSc Clinical Chief of Cardiology Medical Director, CHF/VAD/Transplant James M. Wooten Chair in Cardiology UT Southwestern Medical Center April 28, 2017 Case Presentation 64 year old man Ischemic CM s/p CABG x 2 in past (last 3 years ago) Severely depressed LVEF on echo 1 year ago Symptomatic HF first in 2012 but stabilized on medications Now admitted with SOB x 1 week, no chest pain, weight increased 10 lbs Outpatient medications include carvedilol 6.25 mg bid; Enalapril 5 mg bid; aldactone 12.5 mg/day, lasix 40 mg bid

2 Case (continued) Pertinent admission data BP 100/74, HR 98, JVD 14 cm, lungs clear,? S3, 2+ edema, warm extremities Na 135, BUN 45, Cr 1.5 (3 months ago 1.3), ProBNP 2500 Rx BBL dose reduced; IV furosemide 80 mg bid Makes 1 L urine overnight and AM Cr rises to 1.8 Types of Cardiorenal Syndrome (CRS) Type CRS type 1 (acute) CRS type 2 (chronic) CRS type 3 (acute reno-cardiac syndrome) CRS type 4 (chronic reno-cardiac syndrome) CRS type 5 (secondary) Definition Abrupt worsening of cardiac function leading to kidney injury Chronic abnormalities in cardiac function causing progressive chronic kidney disease Abrupt worsening of renal function causing acute cardiac disorder (e.g. HF, arrhythmia, pulmonary edema) Chronic kidney disease contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of cardiovascular events Systemic condition causing both cardiac and renal dysfunction

3 Worsening Renal Function in HF Outline Epidemiology Causes of AKI in Heart Failure Management of AKI in Heart failure Meta-analysis: Worsening Renal Failure is Associated with Mortality (n=49,890) Damman, EHJ, 2014

4 Renal Function as Important as LVEF (CHARM) Multivariable HR for Risk of CV Death or HF Hospitalization Hillege, Circ, 2006 Improving Renal Function (Cr fall 0.3) is Also a Risk Factor for Adverse Outcomes (before You Consider WRF as a Surrogate Endpoint ) Cr DOSE Trial (NHLBI); N= x 2 factorial High vs Low dose diuretic; Bolus vs. Continuous infusion Brisco, JCF, 2016

5 Persistently Improved Renal Function (IRF) and Outcome U of Penn 903 patients discharged for CHF IRF = 20% improvement GFR 31% have IRF No IRF Persistent IRF (at D/C) Transient IRF (not at D/C) Testani, JCF, 2011 Outline Worsening Renal Function in HF Epidemiology Causes of WRF in Heart Failure Baseline renal function Systemic venous congestion Fall in systemic blood pressure Relative degrees of Right vs. Left congestion Management of AKI in Heart failure

6 Meta-analysis: Risk Factors for Worsening Renal Failure (n=49,890) Damman, EHJ, 2014 Baseline Renal Function is Associated with Risk of Worsening Renal Function (WRF): Meta-Analysis % Patients who Develop WRF Area of circle is proportional to sample size of cohort Baseline Serum Cr (mg/dl) Damman, J Card Failure, 2007

7 Distribution of CVP and its Curvilinear Relationship with egfr 2,557 patients with right heart catheterization Damman, JACC, 2009 Venous Congestion and Worsening Renal Function (Cr 0.3) CVP < 8 CVP 8-16 CVP CVP > patients, Cleveland Clinic Advanced, decompensated HF PA catheter Mullens, JACC, 2009

8 Venous Congestion, not CI, Associated with Worsening Renal Function AUC = 0.73 (p<0.001) Mullens, JACC, 2009 Cardiac Index is Not Driver of Worsening Renal Function in Heart Failure

9 CVP and Renal Dysfunction: Old Lessons Relearned Winton, J Physiology, 1931 If the blood pressure in the renal vein is raised above 10 mm Hg, it retards the urine flow. Firth, Lancet, 1988 Isolated perfused rat kidney GFR (ml/min) Venous Pressure (mm Hg) *

10 VMAC: Systemic Venous Congestion Not Associated with Worsening Renal Function N=238 Cr>0.3 up to 14 days Adapted from Aronson, Eur J Heart Fail, 2013 Larger Drop in Systolic Blood Pressure Contributes to Worsening Renal Failure Pre-RELAX-AHF N=234 Relaxin Voors, Eur J of Heart Fail, 2011

11 Decrease in MAP Associated with Worsening Renal Function Cleveland Clinic N=434 ADHF Right heart cath Dupont, Eur J Heart Fail, 2013 Relative Degree of Right to Left-Sided Congestion: RAP/PCWP ratio and Renal Dysfunction

12 Distribution of RAP/PCWP Ratio in the ESCAPE Trial Drazner et al, Circ HF, 2013 Concordant e.g., RA 11/PCWP 22 Drazner et al, Circ HF, 2013

13 Concordant e.g., RA 11/PCWP 22 RAP/PCWP<1/3 Compensated RV e.g., RA 5/PCWP 30 Drazner et al, Circ HF, 2013 Concordant e.g., RA 11/PCWP 22 RAP/PCWP<1/3 Compensated RV e.g., RA 5/PCWP 30 RAP/PCWP>2/3 Right-Left Equalizer e.g., RA 20/PCWP 24 Drazner et al, Circ HF, 2013

14 Compensated RV Pattern: Low RAP/PCWP Has Smaller RV Drazner, Circ HF, 2013 Compensated RV Pattern: Low RAP/PCWP Has Smaller RV Drazner, Circ HF, 2013

15 Sub-phenotyping HF by RAP/PCWP ratio Compensated RV pattern Low RAP/PCWP ratio: low RAP with high PCWP Erroneously believe patient is compensated Right-Left equalizer High RAP/PCWP ratio: RAP is higher than expected for given PCWP Over-diuresis? renal failure, worse outcome RAP/PCWP Ratio and Renal Function in Advanced Heart Failure Study N Association Cardiac Transplant Research Database 4079 Lower CrCL ESCAPE 215 Lower CrCl Cleveland Clinic 367 Lower egfr Drazner, J Ht Lung Transplant, 2012 Drazner, Circ Heart Failure, 2013 Grodin, AHJ, 2015

16 Increasing RAP/PCWP Quartile is Associated with Reduced egfr Grodin, AHJ, 2015 Increasing RAP/PCWP Quartile is Associated with Reduced egfr Independent of RAP in multivariable analysis Grodin, AHJ, 2015

17 Outline Worsening Renal Function in HF Epidemiology Causes of WRF in Heart Failure Management of AKI in Heart failure Outline Worsening Renal Function in HF Epidemiology Causes of AKI in Heart Failure Management of AKI in Heart failure Does all AKI indicate a need to change therapy? Failed strategies Proposed clinical approach

18 Modifiers of Prognosis Associated with Worsening Renal Function Hemoconcentration (decongestion) Clinical congestion NT-proBNP Medications which block RAAS Modifiers of Prognosis Associated with Worsening Renal Function Hemoconcentration (decongestion) Clinical congestion NT-proBNP Medications which block RAAS Assess clinical context

19 Hemoconcentration During Hospitalization is Associated with Worsening Renal Function Testani, Circ, 2010 In Support of Decongestion: Hemoconcentration is Favorable Prognostic Sign Hemoconcentration Hemoconcentration 2 of 3 of Delta: Hct Albumin Total protein No Hemoconcentration Testani, Circ, 2010

20 Worsening Renal Function in Presence of Hemoconcentraction May Not Be Adverse Risk Factor WRF, + Hemoconcentration No WRF, + Hemoconcentration No WRF, No Hemoconcentration WRF, no Hemoconcentration Testani, Eur J Heart Fail, 2011 Worsening Renal Function in Setting of Low NT-proBNP May Not Increase Risk PROTECT; N=151 RCT: Usual vs. NTproBNP guided WRF = any decrease in GFR by 3 months CV event = Worsening/hosp. HF, ACS, CV Death, Cerebral ischemia, Ventricular arrhythmia Ibrahim, JCF, 2017

21 Discharge Signs of Congestion Modifies Risk of Worsening Renal Function No WRF, + Congestion WRF, No Congestion No WRF, + Congestion WRF, + Congestion N=599 HF admissions Congestion: 1 or more signs of fluid overload at discharge WRF: Increase Cr 0.3 mg/dl Metra, Circ Heart Fail, 2012 Modifiers of Prognosis Associated with Worsening Renal Function Hemoconcentration (decongestion) Clinical congestion NT-proBNP Medications which block RAAS

22 Meta-analysis: RAAS Initiation Reduces Mortality Even in Setting of Worsening Renal Function EPHESUS RALES SAVE SOLVD VaL-HeFT Clark, EHJ, 2013 Worsening Renal Function After ACEi is Not Associated with Increased Mortality (SOLVD) Enalapril, WRF Enalapril, No WRF Placebo, No WRF Placebo, WRF Testani, Circ Heart Fail, 2011

23 Worsening Renal Function with Sprionolactone Use is Not Associated with Mortality (RALES) Vardeny, JACC, 2012 However

24 Worsening Renal Function Following ARB in HFPEF Is Associated with Adverse Outcomes Damman, JACC, 2014 Worsening Renal Function with RAAS inhibitor: HFrEF vs. HFpEF WRF more common with RAAS inhibitor (13% vs 9%) True in both HFrEF and HFpEF WRF with RAAS-inhib HFrEF HR 1.19 ( ) HFpEF HR 1.78 ( ) WRF with Placebo HR 1.48 ( ) HR 1.25 ( ) P interaction Postulated: Difference due to lack of benefit of RAAS inhibitor in HFpEF

25 Outline Worsening Renal Function in HF Epidemiology Causes of WRF in Heart Failure Management of AKI in Heart failure Does all AKI need to change therapy? Failed strategies Proposed clinical approach Failed Therapies for Renal Protection Nesiritide Dopamine Ultrafiltration Adenosine A 1 receptor antagonist Continuous loop diuretics Ularitide (synthetic urodilatin; TRUE-AHF) Serelaxin (human relaxin 2; RELAX-AHF2)

26 Can Echo and BNP Guided Therapy Reduce Risk of Renal Failure in HF? Multicenter observational outpatient study in Italy N=1137 (570 used Echo/BNP and 567 Clinical) Death or Worsening Renal Function Daily Furosemide dose Simioniuc, IJC, 2016 Can Echo and BNP Guided Therapy Reduce Risk of Renal Failure in HF? Multicenter observational outpatient study in Italy N=1137 (570 used Echo/BNP and 567 Clinical) Daily Furosemide dose Await GUIDE-IT Simioniuc, IJC, 2016

27 Outline Worsening Renal Function in HF Epidemiology Causes of WRF in Heart Failure Management of AKI in Heart failure Does all AKI need to change therapy? Failed strategies Proposed clinical approach Proposed Approach for Worsening Renal Function in Decompensated HF Lack of evidence base Look for alternative causes Nephrotoxins (NSAIDs, contrast) Interstitial nephritis (Abx, urine eosinophils) UTI Hydronephrosis Bladder outlet obstruction (amyloid/neuropathy)

28 Proposed Approach for Worsening Renal Function in Decompensated HF Lack of evidence base Look for alternative causes Assess clinical context Severity? (Cr 1.7 or 3.5) Responding to diuretics? Hemodynamics by clinical examination Congested? Right, Left, Both? Perfused? Blood pressure (manual check) Other modifiers Hemoconcentration NT-proBNP RAAS blocker Proposed Clinical Approach for Acute Kidney Injury in Decompensated HF Scenario: Clinically congested, significant in Cr, no alternative cause, not adequately diuresing despite escalation of diuretics Consider: Reduction of BP lowering medications including RAAS inhibitors and BBL Invasively measure hemodynamics Estimation of perfusion adequacy often wrong R>L congestion Inotropes/advanced HF therapies

29 ACC/AHA 2013 CHF Guidelines and PA Catheter (Class IIa- LOE C)..can be useful for carefully selected patients with acute HF who have persistent symptoms despite empiric adjustment of standard therapies and: whose fluid status, perfusion, or SVR or PVR is uncertain whose SBP remains low or is associated with symptoms despite initial therapy whose renal function is worsening with therapy who may require parenteral vasoactive agents who may need consideration of mechanical support/transplantation Summary Worsening renal function in HF associated with adverse outcomes (like low LVEF) Cannot be surrogate (improved renal function also unfavorable) Risk factors Baseline Cr Decrease in BP Age Disproportionate R to L congestion Treatment No evidence base Look for alternative causes Assess clinical context (decongested, probnp, hemoconcentration, maybe RAAS blocker) Sick patient: reduce RAAS/BBL, Right heart cath?

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