Recognizing and Treating Patients with the Cardio-Renal Syndrome

Recognizing and Treating Patients with the Cardio-Renal Syndrome Joachim H. Ix, MD, MAS, FASN Professor of Medicine Chief; Division of Nephrology-Hypertension University of California San Diego 1

Conflicts of Interest None. 2

Outline Why is creatinine often already elevated at presentation in acute decompensated heart failure (ADHF)? On balance, are treatments that improve ADHF but worsen renal function good or bad? Not all worsening renal function is the same. My internist / nephrologist approach to treating ADHF. 3

Outline Why is creatinine often already elevated at presentation in acute decompensated heart failure (ADHF)? On balance, are treatments that improve ADHF but worsen renal function good or bad? Not all worsening renal function is the same. My internist / nephrologist approach to treating ADHF. 4

Traditional Paradigm for Heart Failure-Induced Worsening Renal Function (WRF) Cardiac output Renal perfusion Renal function Low forward flow 5

No Association Between Tertiles of Cardiac Index and egfr, BUN, BUN/Creat, SCr in ADHF 6 Hanberg, JS, et al. JACC 2016;67:2199

No Correlation Between Cardiac Index and Change in egfr During Hospitalization with ADHF CI at Baseline Final CI CI on Optimal Day CI Change from Baseline to Final 7 Hanberg, JS, et al. JACC 2016;67:2199

Traditional Paradigm for Heart Failure-Induced Worsening Renal Function (WRF) Cardiac output Renal perfusion Renal function Low forward flow 8

Change in Intra-Abdominal Pressure is Tightly Correlated with Change in Kidney Function 40 consecutive patients with ADHF 24 of 40 (60%) had intra-abdominal pressure (IAP) > 8mmHg. None had abdominal symptoms. The IAP at admission was correlated with admission Cr. IAP was strongly correlated with serum Cr during the ADHF admission. Cardiac index and PCWP was not different between those with vs. without elevated IAP on admission. 9 Mullens W, et al. JACC 2008; 51: 300-6.

Venous Congestion as a Contributor to Worsening Renal Function (WRF) in Acute Decompensated Heart Failure Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) RCT of 433 patients WRF defined as 20% decline in egfr CVP Cardiac Index These data put venous congestion as a potential central causative factor of WRF in ADHF, and suggest that aggressive treatment of congestion may be a central tenant for treatment ADHF 10

Outline Why is creatinine often already elevated at presentation in acute decompensated heart failure (ADHF)? On balance, are treatments that improve ADHF but worsen renal function good or bad? Not all worsening renal function is the same. My internist / nephrologist approach to treating ADHF. 11

Lower egfr at baseline is common, and strongly associated with poor outcomes in ADHF Decompensated HF, N=118,465 12 Hillege et al, Circulation 2000;102:203

Renal Dysfunction Outperforms Traditional Metrics of Disease Severity for Strength of Association with Mortality Renal These data look at CKD at baseline, and reflect Function the severity of the patient s condition. (egfr) The effects of ADHF treatment on kidney function may be very different. Ejection Fraction 13 Hillege et al, Circulation 2000;102:203

Studied 366 patients with ADHF from the ESCAPE trial who had baseline and discharge pairs of hematocrit, serum albumin, and total protein data. Change in each of these 3 parameters during admission were categorized into tertiles. Hemoconcentration was defined as having 2 of the 3 parameters in the highest tertile. Examined diuretic response, hemodynamic parameters, and survival by hemoconcentration. 14 Testani JM, et al., Circulation 2010; 122: 265-72.

Effects of Treatment for Congestion on Renal Function and Survival No Hemoconcentration (n=102) Hemoconcentration (n=49) P-value Loop diuretic dose 240 (100, 400) 360 (200, 480) 0.03 Weight (kg) 2.7 ± 3.7 6.3 ± 6.6 < 0.001 Rate of wt. loss 0.45 ± 0.68 0.96 ± 0.98 < 0.001 Net fluid loss -3.8 ± 4.2-6.1 ± 6.5 0.04 Rate fluid loss -0.56 ± 0.64-0.83 ± 0.74 0.04 15 Testani JM, et al., Circulation 2010; 122: 265-72.

Effects of Treatment for Congestion on Renal Function and Survival Association of Hemoconcentration with Association of Hemoconcentration with Risk Odds of Worsened Renal Function of Survival at 180 Days ( 20% decline in egfr during admission) HR 0.31(0.06, 0.74) p=0.016 OR 5.3 (2.4, 11.7) p< 0.0001 16 Testani JM, et al., Circulation 2010; 122: 265-72.

The Clinical Significance of Change in egfr Differs if it Reflects Initiation of an ACE-Inhibitor Investigators conducted post-hoc analysis of the SOLVD Trial 6337 patients with EF < 35%, Cr 2.5 mg/dl at entry, randomized to enalapril vs. placebo. Worse renal function (WRF) defined as 20% decrease in egfr from BL to day 14. Prior analyses had already demonstrated that both egfr at baseline and WRF were strongly associated with death. The focus of this analysis was to evaluate if WRF had similar clinical implications in the enalapril vs. placebo group. 17 Testani JM, et al., Circ. Heart Fail. 2011; 4: 685-91.

The Clinical Significance of Change in egfr Differs if it Reflects Initiation of an ACE-Inhibitor Placebo (282 / 3199) Enalapril (324 / 3178) HR (95% CI) for Risk of Death* P interaction *Adjusted for age, race, EF, heart rate, DBP, NYHA class, serum Na, baseline egfr, diabetes, HTN, stroke, MI, loop diuretic use, K sparing diuretic use, digoxin use, and beta blocker use. 18 Testani JM, et al., Circ. Heart Fail. 2011; 4: 685-91.

The Clinical Significance of Change in egfr Differs if it Reflects Initiation of an ACE-Inhibitor HR (95% CI) for Risk of Death* Placebo (282 / 3199) 1.4 (1.1, 1.8) p< 0.01 Enalapril (324 / 3178) P interaction *Adjusted for age, race, EF, heart rate, DBP, NYHA class, serum Na, baseline egfr, diabetes, HTN, stroke, MI, loop diuretic use, K sparing diuretic use, digoxin use, and beta blocker use. 19 Testani JM, et al., Circ. Heart Fail. 2011; 4: 685-91.

The Clinical Significance of Change in egfr Differs if it Reflects Initiation of an ACE-Inhibitor HR (95% CI) for Risk of Death* Placebo (282 / 3199) 1.4 (1.1, 1.8) p< 0.01 Enalapril (324 / 3178) 1.0 (0.8, 1.3) p=1.00 P interaction *Adjusted for age, race, EF, heart rate, DBP, NYHA class, serum Na, baseline egfr, diabetes, HTN, stroke, MI, loop diuretic use, K sparing diuretic use, digoxin use, and beta blocker use. 20 Testani JM, et al., Circ. Heart Fail. 2011; 4: 685-91.

The Clinical Significance of Change in egfr Differs if it Reflects Initiation of an ACE-Inhibitor HR (95% CI) for Risk of Death* Placebo (282 / 3199) 1.4 (1.1, 1.8) p< 0.01 Enalapril (324 / 3178) 1.0 (0.8, 1.3) p=1.00 P interaction 0.04 *Adjusted for age, race, EF, heart rate, DBP, NYHA class, serum Na, baseline egfr, diabetes, HTN, stroke, MI, loop diuretic use, K sparing diuretic use, digoxin use, and beta blocker use. 21 Testani JM, et al., Circ. Heart Fail. 2011; 4: 685-91.

The Clinical Significance of Change in egfr Differs if it Reflects Initiation of an ACE-Inhibitor HR (95% CI) for Risk of Death* Placebo (282 / 3199) 1.4 (1.1, 1.8) p< 0.01 Enalapril (324 / 3178) 1.0 (0.8, 1.3) p=1.00 P interaction 0.04 *Adjusted for age, race, EF, heart rate, DBP, NYHA class, serum Na, baseline egfr, diabetes, HTN, stroke, MI, loop diuretic use, K sparing diuretic use, digoxin use, and beta blocker use. 22 Testani JM, et al., Circ. Heart Fail. 2011; 4: 685-91.

Acute Rise in Serum Creatinine During Acute Heart Failure Good thing Induced loss of egfr Bad thing Spontaneous loss of egfr Diuresis in HF Decongestion Hemoconcentration RAAS antagonism Untreated cardiorenal Sepsis Nephrotoxins 23 Outcomes Better Outcomes Worse

Outline Why does creatinine often already up at presentation of acute decompensated heart failure (ADHF)? On balance, are treatments that improve ADHF but worsen renal function good or bad? Not all worsening renal function is the same. My internist / nephrologist approach to treating ADHF. 24

If Treating Congestion is Good, then what about Ultrafiltration? 25

Costanzo et al. JACC 2007 UNLOAD Trial 200 inpatients with ADHF, randomized to UF vs IV diuretic (2X pre-hospital dose) More weight loss with UF Less rehospitalizations with UF 26

CARESS-HF Required WRF as an inclusion criteria ( 0.3 mg/dl in last 12 weeks). Fixed UF rate (-200cc/hr for everyone regardless of hemodynamics) Used a more aggressive diuretic protocol. 46% received metolazone within first 7 days Only 6% needed UF for lack of response 27 Bart BA, et al. NEJM 2012;367:2296

CARRESS-HF: Equal Amount of Weight Loss; Creatinine Higher in UF Arm 28 Bart BA, et al. NEJM 2012;367:2296

CARESS-HF 29 Bart BA, et al. NEJM 2012;367:2296

Not all worsening renal failure in treatment of ADHF is the same ADHF Venous Congestion Low SBP Low CI High Ang. II Worse Renal Function ~ 90% ~ 10% Diuresis Hemoconcentration Afterload reduction ACE inhibition http://www.medical-labs.net/muddy-brown-granular-casts-2892/ https://www.idexx.eu/france/products-and-solutions/analysers/sedivue-dx/sedivue-bilder/ 30

Not all worsening renal failure in treatment of ADHF is the same. Acute Tubule Necrosis (ATN) 31 http://slideplayer.com/slide/4562410/

Outline Why does creatinine often already up at presentation of acute decompensated heart failure (ADHF)? On balance, are treatments that improve ADHF but worsen renal function good or bad? Not all worsening renal function is the same. My internist / nephrologist approach to treating ADHF. 32

My Approach To Treatment of ADHF with Renal Dysfunction Stable or Improved Renal Function (in 60-80%) ADHF/ Congestion This has to be treated! 33 Give high-dose loop diuretic (2.5x) Add metolazone to block DCT Worsened renal function (in 20-40%) Still congested Some worsening in egfr but decongested (20-30% decline) Deal with it Call your Renal friends Renal function keeps worsening

My Advice for Avoiding Acute Tubule Necrosis Understand the need to be aggressive in treating congestion: Don t let CKD or modest WRF stop your patient from getting adequate diuresis or ACE inhibition. Don t be too eager to discharge and hope for additional improvements in clinical stats as an out-patient. Adding treatments may take a step approach when Cr has been steady for a few days before adding on additional therapies. 34

My Advice for Avoiding Acute Tubule Necrosis Understand that ADHF are at high risk for ATN Poor renal perfusion ACE inhibition further decreases GFR BP often low. 35

My Advice for Avoiding Acute Tubule Necrosis Recognize that any additional insults are very likely to cause ATN Avoid NSAIDs. Think and rethink need for radiocontrast, especially in diabetic patients. If contrast is needed, consider holding ACE and diuretics for 48 hours before and after. 36

My Advice for Avoiding Acute Tubule Necrosis Dialysis or ultrafiltration may be needed. But we lose the ability to manage momentary changes in venous filling, and ATN risk may be particularly high. It may be needed, but should be treatment of last resort. 37

Thank you Pranav Garimella, MD, MS Assistant Professor Division of Nephrology-Hypertension UC San Diego Steven Coca, MD Associate Professor Division of Nephrology Icahn School of Medicine at Mount Sinai All of you for your attention an interest 38