The Cardiorenal Syndrome A Cardiologist’s Perspective

J Thomas HeywoodDirector, Heart Failure Program

Scripps Clinic, La Jolla, California

Disclosures

Consulting: Medtronic

Research: St Jude, Medtronic,

Speakers Bureau: Otsuka, Actelion, Medtronic

High Prevalence of Renal Dysfunction and Its Impact on Outcome in 118,465 Patients Hospitalized With Acute Decompensated Heart Failure: A Report From the ADHERE Database J. Thomas Heywood MD et al J Card Failure Sept 2007

65%Have at least Moderate renaldysfunction

BUN 43(n=32220)

Inpatient mortality from ADHERE Registry Based on admission BUN, creatinine and BP

8.35%(n=67640)

SBP 115(n=6697)

15.30%(n-1863)

5.63%(n-4834)

Cr 2.75(n-1862)

13.23%(n-1270)

19.76%(n-592)

2.88%(n=24469)

SBP 115(n=2,702)

5.67%(n=3882)

2.31%(n=20820)

<

<

<

<

Analysis of patients in the National Acute Decompensated Heart Failure National Registry (ADHERE)BUN=blood urea nitrogen, Cr=serum creatinine, SBP-systolic blood pressureFonarow GC et al. J Cardiac Fail 2003;9(suppl 1):S79.

Why is renal function abnormal in patients with heart failure?

The cardiorenal syndrome (CRS)Definition

• Worsening renal function (> 25% increase in creatinine or BUN during treatment for acute decompensation)

• Difficulty in diuresis without worsening renal function• ACE intolerance due to hypotension or hyperkalemia in

severe heart failure• Chronic renal insufficiency complicating HF therapy

Heart failure with…

Role of the kidney in congestive heart failure: Relationship of CI to kidney function

Group An=12

Group Bn=13

Group C n=9

Pvalue

Car. Index 2.4±.15 1.78±.17* 1.35±.14* * <.001

SVR 1313±296 1866±455* 2464±956** * <.01** <.001

RA 7±8 10±5 14±8 ns

Wedge 19±11 29±7* 30±8* * <.01

Ljungman, Cody Drugs 1990;39 Suppl 4:10-21

Role of the kidney in congestive heart failure: Relationship of CI to kidney function

Ljungman, Cody Drugs 1990;39 Suppl 4:10-21

0

100

200

300

400

500

A, CI> 2 B, CI>1.5<2.0

C, CI <1.5

Renal BFRV Resistance

Renal Blood Flow

Renovascular

Resistance

RBF, p<.05 with Group A

RVR, p<.01 with Group A

Role of the kidney in congestive heart failure: Relationship of CI to kidney function

Ljungman, Cody Drugs 1990;39 Suppl 4:10-21

0

10

20

30

40

50

60

70

A, CI> 2 B, CI>1.5 <2.0 C, CI <1.5

GFRBUN

GFR/

BUN

CI, p<.001 with Group A BUN, p<.01 with Group A

Creatinine was not different between the groups. BUN better indicated low CI and GFR than creatinine

`

Am J Cardiol 2006:97:1759

Effect of increasing central venous pressure on GFR in dogs, constant BP

0.5

0.8

1.1

1.4

0 6.25 12 18.75 25 0 Central Venous Pressure

GFR

ml/minP< .05

P< .05 Raised Venous Pressure: A direct cause of renal sodium retention

Firth et al Lancet 5/7/88

mm Hg

High CVP significantlyimpairs GFR

Effect of Increased Renal Venous Pressure on Renal Function

• Swine where anesthetized, instrumented and a unilateral nephrectomy preformed.

• In the remaining kidney the renal vein was constricted in half the animals to obtain a renal venous pressure of 30, the other animals served as controls

Doty J et al J of Trauma: Injury, Infection and Critical Care 1999 47:1000-1005

0

5

10

15

20

25

30

RA Bloodflow Index

GFR Aldosterone ReninActivity

ControlRV Constric

P <.05 between groups

Renal Decapsulation in the Prevention of Post-Ischemic Oliguria

• 15 rhesus monkeys, 1 hour suprarenal aortic clamping to produce ATN, after which the renal capsule was stripped from one kidney. The ureters of each kidneys were catheterized to collect urine for creatinine, urea and free water.

Stone HJ Annals of Surgery 1977:343-355

0

1

2

3

4

5

6

7

Cr Cl Urea Cl Free Water

DecapsuledControl

P <.01

Mullens, W. et al. J Am Coll Cardiol 2009;53:589-596

Prevalence of Worsening Renal Function During Hospitalization According to Categories of Admission CVP, CI, SBP, and PCWP

Treatment of the Cardiorenal Syndrome 5 important questions…

• What is the fluid status?• Is the blood pressure adequate for renal perfusion?• What is the cardiac output?• Is there evidence of high central venous pressure?• Is there intrinsic renal disease?

Hypovolemic Cardiorenal Syndrome

• Overdiuresed or intercurrent illness results in volume loss and renal dysfunction

• Give fluids, stop diuretics and IV vasodilators• Often a reluctance to give fluids to HF patients

but it may be critical in this situation and time is of the essence to avoid irreversible renal damage

Too Dry!!!

CRS due to high central venous pressure

• Poor renal perfusion due to high central venous pressure• Usually CVP > 15-20 mm Hg coupled with reduced blood

pressure• Diuretics often held because of worsening renal function

and misguided idea of “ intravascular volume depletion”• Continue diuretics to reduce central venous pressure• Ultrafiltration

Too Wet!!!

CRS with vasoconstriction

• Low CO and hence renal hypoperfusion due to HF mediated vasoconstriction (Ang II, endothelin induced increased afterload)

• CO is low and SVR high, often over 1800-2000• ACEI and vasodilators very useful since CO can increase

significantly if afterload normalized. Actual improvement in renal function may be seen

• May need temporary inotropic support if systolic BP <80 as vasodilators are added

Clamped Down!!!

ACEI play a complex role in renal function in HF

• May improve CO in some patient and hence increase effective renal perfusion• ACEI may lower BP to the point where effective renal perfusion is impaired • With chronic renal disease, there is hyperfiltration in the remaining nephrons. ACEI decreases efferent arteriole constriction and hence decreases glomerular capillary pressure which may preserve renal function longterm• This may result in a 10-20% increase in creatinine, but over the long term renal function is preserved

Circulation 2001:104:1985-1991

ACEI intolerance in low CO, low SVR states

Circulation 2001:104:1985

GFR Maintained

GFR Declines

CRS with normal SVR but low CO or BP

“ No Pump!!!”

• CRS due to inadequate renal perfusion because of low CO and/or BP, Nml SVR!!!

• Inotropes, Pressors, Temporary circulatory support

• LVAD

“Although there is no serum creatinine level per se that contraindicates ACE inhibitor therapy, greater increases in serum creatinine occur more frequently when ACE inhibitors are used in

patients with underlyingchronic renal insufficiency.”

Heart Mate 2

Severe Renal Dysfunction Complicating Cardiogenic Shock is not a contraindication to Mechanical Support as a Bridge to Transplant

Khot UN et al JACC 2003

CRS with vasodilation

• Renal hypoperfusion due to low perfusion; CO may be normal but SVR and BP low

• Vasodilators worsen BP and hence renal perfusion• Stop of ACEI, especially if SVR is low• Rule out sepsis• Pressors, Inotropes, ? Vasopressin• Consider transplant or ventricular assist device if renal

dysfunction is felt to be reversible

“Vasodilated!!”

A Prospective Randomized Trial of Arginine Vasopressin in the Treatment of Vasodilatory Shock after Assist Device Placement

• 10/23 VAD patients with low blood pressure and increased cardiac index• Despite pressors, SVR still decreased• 5 received saline placebo for 15 minutes and 5 vasopressin (.1 Units/min, 3 patients in placebo group were blindly crossed over• No change in BP in placebo group• MAP increased from 61 to 87 in the Vaso group with increase in SVR from 729 to 1374, with significant reduction in NE dose• NE was able to be weaned off in 4/5 patients within 15 minutes

Argenziano et al Circ 1997 Suppl II 290

CRS with normal CO and SVR

• Consider intrinsic renal disease (IRD) or diuretic resistance syndrome, renal artery stenosis

• Probable IRD when long hx of HTN and/or diabetes, look for proteinuria, renal artery stenosis

• Trial of loop diuretic infusion, combination with distal tubular diuretic

• Add nesiritide• Consider ultrafiltration

“It’s the Kidneys,Not the Heart!!!!””

Renal Adaptation to Diuretics

Ellison DH. Am J Kidney Dis. 1994;5:623.

Stanton and Kaissling Am J Physiol 1988 255:F1269

Invasive hemodynamic monitoring should be considered in a patient:• who is refractory to initial therapy,

• whose volume status and cardiac filling pressures are unclear,

• who has clinically significant hypotension (typically SBP !80 mm Hg) or

worsening renal function during therapy, Or • who is being considered for cardiac transplant and needs assessment of degree and reversibility of pulmonary

hypertension, Or in whom documentation of an adequate hemodynamic response to the

inotropic agent is necessary when chronic outpatient infusion is being considered. (Strength of Evidence 5 C)

HFSA Guildelines 2010

Cardiac Output = VTI x Area of Outflow Tract x Heart Rate 8cm/sec x 3cm x 80 beats/min = 1920 ml/min, 1.9 L/min

Hemodynamic Echo-The Noninvasive swan• Right Atrial pressure (Inferior Vena Cava)• Pulmonary Artery Pressure (TR Velo + RA)• Estimated mean left atrial pressure (E/Eʹ)• Cardiac Output (VTI x Area x HR)• Systemic Vascular Resistance

(MAP-RA)x80/CO130/70 = Mean 130+140/3= 90(90-20) x 80/1.9= 5600/1.9 = SVR approx 2800 i.e. vasoconstricted

Case Study

• 56 yo male with ICM, CABG 1998, ICD 2001 EF 10%• Dec 2011 admitted with AF another hospital• Dec 19 Admitted Scripps for dyspnea, angioplasty of OM2,

Diagonal and PDA grafts, RA 15, PA 64/34, Wedge 20, Fick 2.5 L/min, PA Sat 54%

• Discharge Furo 20, Carvedilol 3.125 bid, Lis 2.5• wt 77.4 Kg

Mr CB

Did well for one week, admitted another hospital for pneumonia

• Seen post discharge and digoxin was started for Afib, EF 7% referred back to Scripps

• On Admission, Dyspneic, weight 75 KG• Gen- A/Ox3 but very fatigued• Neck- JVD to jawline, (+)AJR• Heart- Irreg, tachy, 105bpm, 2/6 systolic murmur• Lungs- CTAB• Ext- no edema, cool to touch

Mr CB 1/12 creatinine 1.8• 1/13 Echo EF 14%, PA sys 48, RA 10, Ascited, LVOT 6

cm• 1/13-14 attempted to diuresis, poor UO, Creat 2.2• 1/16 Cardioverted, CRT placed• 1/17 Creat 2.9, 350 cc urine/24hr HF consult• BP 80-90 systolic, cold extremities-Cardiogenic Shock

Initial Swan results in ICU

• RA = 22• RV = 43/22• PAP = 41/26(30)• PCWP = 22• CO/CI = 1.87/1.0 by Fick

• PA sat 33%,

What to do?

Intervention

• Dobutamine IV 5 mcg/kg/min – Titrate to SBP>90

• Dopamine IV 3 mcg/kg/min• Nitroprusside IV 0.5 mcg/kg/min

– maintain SVR 1200-1500– Hold for SBP<90

• Lasix and Zaroxolyn for diuresis

PACVPCO/CISVR

PACVPCO/CISVR

24 hours later…

• CO = 6 L/min• UOP = 6 L overnight (325 mL over the

prior 24 hours)

• Inotropes weaned• Captopril initiated, uptitrated over next 24

hours

Mr TW

• 62 yo male with severe nonischemic cardiomyopathy (alcohol abuse and long standing insulin dependant diabetes)

• Seen in HF Clinic first time 8/25/08 following BIV pacer• Feeling terrible, dizzy BP 70/50• neck veins to the jaw, Very Loud, palpable S3

• Intermittent capture of LV and RV by device • Paced beats are very wide, wider than prior to device

• Readmitted 12 days later for confusion, possible stroke

• BP 100/70 JVP 8, • Creatinine 2.6• Given fluids and placed on milrinone

Very difficult to titrate meds because of combination of low blood pressure, renal dysfunction and high serum potassium,

Could not tolerate spironolactone due to hyperkalemia

Not a transplant candidate-poor social support, advanced diabetesd, BKA

Left atrial pressure monitor inserted 12/08

60

Implantable Components HeartPOD® (Physiologically Optimized Dosimeter) ISL

Implantable Communications Module (ICM)

Lead

Sensor Module

Proximal Anchor

Distal Anchor

Sensor Diaphragm ~ 3 mm

Measures• LAP• IEGM• Core

Temp

Implantable Sensor Lead (ISL)

HeartPOD® SystemPatient Advisory Module (PAM)

LARA

SAVACOR, INC

Modified PDA• Powers implant through

clothing• Atmospheric reference• Stores telemetry • Alerts patient to monitor• ‘DynamicRX®’ instructs

• Meds• Activity• Clinician contact

based on LAP values and physician’s prescription

Very Low Low Optimal High Very High

LAP 0-8 9-17 18-30 31-39 40-50

Torsemide Hold 10 bid 20 bid 30 bid 30 bid call

Mean LAP 31 mm

Very Low Low Optimal High Very High

LAP 0-8 9-17 18-30 31-39 40-50

Torsemide Hold 10 bid 20 bid 30 bid 30 bid call

Mean LAP 31 mm

Very Low Low Optimal High Very High

LAP 0-4 5-12 13-23 24-39 40-50

Torsemide Hold 10 bid 20 bid 30 bid 30 bid call

Mean LAP20.7

Very Low Low Optimal High Very High

LAP 0-4 5-12 13-23 24-39 40-50

Torsemide Hold 10 bid 20 bid 30 bid 30 bid call

Mean LAP 28 mm

Very Low Low Optimal High Very High

LAP 0-4 5-12 13-19 20-39 40-50

Torsemide Hold 10 bid 20 bid 30 bid 30 bid call

Mean LAP16.5

12/14/09 1/26/10 4/19/10 6/16/10 8/19/10

Weight 155 159 158 160 157

Creatinine 3.8 2.2 2.0 1.8 1.9

BUN 100 46 47 42 42

Profiles of the Cardiorenal Syndrome

CRS due to: Fluid Status

COCI

SVR Proteinuria Treatment

Too Dry!!! Dry Low Nml or high None Fluids, stop diuretics

Too Wet!!!(high CVP)

Wet Nml Nml None Continuous diuretic infusion, distal tubular diuretic, ultrafiltration

Too Clamped Down!!!

Wet or Nml

Low High None ACEI, Nitroprusside,Nesiritide, Relaxin

Vasodilated!!!Nml or

wetNml orhigh

Low None Stop ACEI, Pressors, VasopressinInotropes, VAD

No Pump!!!Wet or

NmlLow Nml None Inotropes,

VasopressorsBalloon PumpLVAD

Intrinsic Renal Disease/Diureti

c Resistance

Wet Nml Nml None Continuous diuretic infusion, distal tubular diuretic, ultrafiltration

Volume Management

Diuretics to increasesodium loss and decreasevenous pressures

Concept of Plasma Refill Rate in ADHF

Redefining the Therapeutic Objective in Decompensated Heart Failure: Hemoconcentration as a Surrogate for Plasma Refill Rate Boyle and Sbotka J Card Failure May 2006

Diuretics to increasesodium loss and decreasevenous pressures

Concept of Plasma Refill Rate in ADHF

The prognostic importance of different definitions of worsening renal function in CHF

Risk of death or

Hospitalization >

10 days

S Gottlieb et al J Card Failure 6/02

100

80

60

40

20

0> 0.1 > 0.2 > 0.3 > 0.4 > 0.5

Increase in Creatinine

SensitivitySpecificity

HemodynamicChanges

No Hemoconcentration Hemoconcentration P value

RA pressure -2.8±5.6 -5.4± 0.031

Pulm Art Sys Pres -9.0±12.4 -14.4±10.8 0.124

Wedge Pressure -6.2±8.3 -12.6±9.6 0.015

No Hemoconcentration

Hemoconcentration

Diuretic Optimization Strategies Evaluation in Acute

Heart Failure (DOSE)G. Michael Felker, MD, MHS, FACCChristopher M. O’Connor, MD, FACC

on behalf of the

NHLBI Heart Failure Clinical Research Network

Secondary Endpoints:Low vs. High Intensification

Low High P value

Dyspnea VAS AUC at 72 hours 4478 4668 0.041

% free from congestion at 72 hrs 11% 18% 0.091

Change in weight at 72 hrs -5.3 lbs -8.2 lbs 0.011

Net volume loss at 72 hrs 3575 mL 4899 mL <0.001

% Treatment failure 37% 40% 0.56

% with Cr increase > 0.3 mg/dL at 72 hrs

14% 23% 0.041

Length of stay, days (median) 6 5 0.55

Changes in Creatinine over Time*:High vs. Low

1.45

1.5

1.55

1.6

1.65

1.7

1.75

1.8

0 1 2 3 4 7 60Time (days)

Low High

Cre

atin

ine

(mg/

dL)

p = 0.85p = 0.07

p = 0.28

p = 0.59

p = 0.34

p = 0.81

*P values are for change in creatinine from baseline

Changes in Creatinine over Time*:High vs. Low

1.45

1.5

1.55

1.6

1.65

1.7

1.75

1.8

0 1 2 3 4 7 60Time (days)

Low High

Cre

atin

ine

(mg/

dL)

p = 0.85p = 0.07

p = 0.28

p = 0.59

p = 0.34

p = 0.81

*P values are for change in creatinine from baseline

Proportion with Worsening Renal Function: High vs. Low

0%

5%

10%

15%

20%

25%

0 1 2 3 4 7 60Time (days)

Low High

% w

ith Δ

Cr >

0.3

mg/

dL

Death, Rehospitalization, or ED Visit

HR for Continuous vs. Q12 = 1.19 95% CI 0.86, 1.66, p = 0.30

HR for High vs. Low = 0.83 95% CI 0.60, 1.16, p = 0.28

0

0.1

0.2

0.3

0.4

0.5

0.6

0 10 20 30 40 50 60

Days

Prop

ortio

n w

ith D

eath

, Reh

osp,

or E

D v

isit

High Low

0

0.1

0.2

0.3

0.4

0.5

0.6

0 10 20 30 40 50 60

Days

Prop

ortio

n w

ith D

eath

, Reh

osp,

or E

D Vi

sit

Continuous Q12

Original Article Ultrafiltration in Decompensated Heart Failure with

Cardiorenal Syndrome

Bradley A. Bart, M.D., Steven R. Goldsmith, M.D., Kerry L. Lee, Ph.D., Michael M. Givertz, M.D., Christopher M. O'Connor, M.D., David A. Bull, M.D., Margaret M. Redfield, M.D., Anita Deswal, M.D., M.P.H., Jean L. Rouleau, M.D., Martin M.

LeWinter, M.D., Elizabeth O. Ofili, M.D., M.P.H., Lynne W. Stevenson, M.D., Marc J. Semigran, M.D., G. Michael Felker, M.D., Horng H. Chen, M.D., Adrian F.

Hernandez, M.D., Kevin J. Anstrom, Ph.D., Steven E. McNulty, M.S., Eric J. Velazquez, M.D., Jenny C. Ibarra, R.N., M.S.N., Alice M. Mascette, M.D., Eugene

Braunwald, M.D., for the Heart Failure Clinical Research Network

N Engl J MedVolume 367(24):2296-2304

December 13, 2012

Literary Last Note• “All happy families are all alike, all unhappy families are unhappy in

their own way.” Anna Karenina Leo Tolstoy

All patients compensated HF patients are alike, all patients with cardiorenal syndrome are unhappy in their own way.