The Cardiorenal Syndrome
A Cardiologist’s Perspective
J Thomas Heywood
Director, 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 renal
dysfunction
Inpatient mortality from ADHERE Registry
Based on admission BUN, creatinine and BP
<

BUN 43
(n=32220)
2.88%
(n=24469)
<

<
2.31%
(n=20820)
15.30%
(n-1863)
SBP 115
(n=2,702)
5.67%
(n=3882)
8.35%
(n=67640)
<
13.23%
(n-1270)
SBP 115
(n=6697)
Cr 2.75
(n-1862)


5.63%
(n-4834)
19.76%
(n-592)
Analysis of patients in the National Acute Decompensated Heart Failure National Registry (ADHERE)
BUN=blood urea nitrogen, Cr=serum creatinine, SBP-systolic blood pressure
Fonarow 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
Heart failure with…
• 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
Role of the kidney in congestive heart failure:
Relationship of CI to kidney function
Group A
n=12
Group B
n=13
Group C
n=9
P
value
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
RBF, p<.05 with Group A
500
Renal
Blood
Flow
400
Renovascular
200
Resistance
100
RVR, p<.01 with Group A
300
0
Renal BF
RV Resistance
A, CI> 2
B, CI>1.5
<2.0
Ljungman, Cody Drugs 1990;39 Suppl 4:10-21
C, CI <1.5
Role of the kidney in congestive heart
failure: Relationship of CI to kidney function
70
CI, p<.001 with Group A
BUN, p<.01 with Group A
GFR/BUN
60
50
40
GFR
BUN
30
20
10
0
A, CI> 2
B, CI>1.5 <2.0
C, CI <1.5
Creatinine was not different between the groups. BUN better indicated
low CI and GFR than creatinine
Ljungman, Cody Drugs 1990;39 Suppl 4:10-21
`
Am J Cardiol 2006:97:1759
Effect of increasing central venous pressure
on GFR in dogs, constant BP
1.4
GFR
P< .05
Raised Venous
Pressure: A
direct cause of
renal sodium
retention
1.1
ml/min
P< .05
0.8
Firth et al Lancet
5/7/88
High CVP significantly
impairs GFR
0.5
0
6.25
12 18.75
25
mm Hg
0
Central Venous Pressure
Effect of Increased Renal Venous Pressure
on Renal Function
Doty J et al J of Trauma: Injury, Infection and Critical Care 1999 47:1000-1005
• 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
30
P <.05 between groups
25
20
15
Control
RV Constric
10
5
0
RA Blood
flow Index
GFR
Aldosterone
Renin
Activity
Renal Decapsulation in the Prevention of
Post-Ischemic Oliguria
Stone HJ Annals of Surgery 1977:343-355
• 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.
7
6
P <.01
5
4
Decapsuled
Control
3
2
1
0
Cr Cl
Urea Cl
Free Water
Prevalence of Worsening Renal Function During Hospitalization
According to Categories of Admission CVP, CI, SBP, and PCWP
Mullens, W. et al. J Am Coll Cardiol 2009;53:589-596
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
Too Dry!!!
• 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
CRS due to high central venous pressure
Too Wet!!!
• 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
CRS with vasoconstriction
Clamped
Down!!!
• 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
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
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 underlying
chronic 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
“Vasodilated!!”
• 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
A Prospective Randomized Trial of Arginine
Vasopressin in the Treatment of Vasodilatory
Shock after Assist Device Placement
Argenziano et al Circ 1997 Suppl II 290
• 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
CRS with normal CO and SVR
“It’s the
Kidneys,
Not the
Heart!!!!””
• 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
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/CO
130/70 = 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
PA
CVP
CO/CI
SVR
PA
CVP
CO/CI
SVR
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
Implantable Components
HeartPOD® (Physiologically Optimized Dosimeter) ISL
Lead
Implantable
Sensor
Lead (ISL)
Sensor
Module
Distal
Anchor
Proximal
Anchor
Implantable
Communications
Module (ICM)
Sensor
Diaphragm
~ 3 mm
Measures
•LAP
•IEGM
•Core Temp
60
HeartPOD® System
Patient Advisory Module (PAM)
SAVACOR, INC
Modified PDA
•Powers implant through
clothing
•Atmospheric reference
•Stores telemetry
•Alerts patient to monitor
RA
LA
•‘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 LAP
20.7
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 LAP
16.5
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
CO
CI
SVR
Proteinuria
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
Nml or
high
Low
None
Vasodilated!!!
Nml or
wet
Stop ACEI,
Pressors, Vasopressin
Inotropes, VAD
Low
Nml
None
No Pump!!!
Wet or
Nml
Inotropes,
Vasopressors
Balloon Pump
LVAD
Wet
Nml
Nml
None
Continuous diuretic
infusion, distal tubular
diuretic, ultrafiltration
Intrinsic Renal
Disease/Diureti
c Resistance
Treatment
Volume Management
Concept of Plasma Refill Rate in ADHF
Diuretics to increase
sodium loss and decrease
venous pressures
Redefining the Therapeutic Objective in
Decompensated Heart Failure: Hemoconcentration
as a Surrogate for Plasma Refill Rate Boyle and Sbotka J Card Failure May 2006
Concept of Plasma Refill Rate in ADHF
Diuretics to increase
sodium loss and decrease
venous pressures
The prognostic importance of different definitions
of worsening renal function in CHF
Sensitivity
100
Risk of death
or
Hospitalization
>
10 days
Specificity
80
60
40
20
0
> 0.1
> 0.2 > 0.3
> 0.4
Increase in Creatinine
S Gottlieb et al J Card Failure 6/02
> 0.5
Hemodynamic
Changes
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
Hemoconcentration
No Hemoconcentration
Diuretic Optimization
Strategies Evaluation in Acute
Heart Failure (DOSE)
G. Michael Felker, MD, MHS, FACC
Christopher 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
-5.3 lbs
-8.2 lbs
0.011
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
6
5
0.55
Change in weight at 72 hrs
Net volume loss at 72 hrs
Length of stay, days (median)
Changes in Creatinine over Time*:
High vs. Low
1.8
p = 0.34
1.75
Low
High
p = 0.59
1.7
Creatinine (mg/dL)
p = 0.85
1.65
p = 0.07
p = 0.81
p = 0.28
1.6
1.55
1.5
1.45
0
1
2
3
Time (days)
*P values are for change in creatinine from baseline
4
7
60
Changes in Creatinine over Time*:
High vs. Low
1.8
p = 0.34
1.75
Low
High
p = 0.59
1.7
Creatinine (mg/dL)
p = 0.85
1.65
p = 0.07
p = 0.81
p = 0.28
1.6
1.55
1.5
1.45
0
1
2
3
Time (days)
*P values are for change in creatinine from baseline
4
7
60
Proportion with Worsening Renal Function:
High vs. Low
25%
Low
% with Δ Cr > 0.3 mg/dL
20%
High
15%
10%
5%
0%
0
1
2
3
Time (days)
4
7
60
Death, Rehospitalization, or ED Visit
Proportion with Death, Rehosp, or ED Visit
0.6
0.5
Continuous
Proportion with Death, Rehosp, or ED visit
HR for Continuous vs. Q12 = 1.19
95% CI 0.86, 1.66, p = 0.30
Q12
0.4
0.3
0.2
0.1
0
0
10
20
30
Days
40
50
60
HR for High vs. Low = 0.83
95% CI 0.60, 1.16, p = 0.28
0.6
High
0.5
Low
0.4
0.3
0.2
0.1
0
0
10
20
30
Days
40
50
60
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 Med
Volume 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.