1. The Cardio-Renal Syndrome Stephen L. Rennyson MD

2. Clinical Presentation
68 y.o. man with iCMO admitted with volume overload consistent with CHF exacerbation
Admitted 2 weeks prior -- similar presentation
Discharged with appropriate CHF regimen, furosemide diuretic
Laboratory Studies
Sodium 132
Creatinine 1.8
Hemoglobin 9.8
Albumin 2.2

3. Placed on BiPap in the ED, given 120 mg of iv Lasix, transferred to CICU . . . Started NTG gtt
Initial success of 500 cc urine output
Morning laboratory studies show creatinine rising
Midnight dose of lasix produced little urine output
Blood pressure falling . . .

4. Cardio-Renal Syndrome
Background
Pathophysiology
Management Options
Case

5. Congestive Heart Failure
Epidemiology changing from acute management to managing the chronicity of cardiac dysfunction
An indicence of 5 million persons
Responsible for over 1 million yearly hospitalizations
280,000 deaths annually

6. Comorbid Conditions . . . Associated with a worse prognosis
Anemia (Hb < 10.0)
Cirrhosis
Peripheral Vascular Disease
Hyponatremia (<135)
Renal failure
N Engl J Med 2006; 355: July 20, 2006

7. Cardiovascular Outcomes with renal dysfunction
Stratified by GFR
Cumulative incidence
Cardiovascular death
Unplanned ADHF admission
reduced LVEF (LVEF<=40%)
Stratified by GFR
LV systolic function (LVEF>40%)
Hillege, H. L. et al. Circulation 2006;113:

8. Best predictors of outcome:
ADHERE Registry
Registry of Acute Decompensated Heart Failure (ADHF)
105,000 patient registry
QOC study evaluating variations in CHF treatment
Best predictors of outcome:
BUN
Creatinine

9. Cardio-Renal Syndrome
Most Simplistic Description:
Associated loss of renal function in the setting of advanced CHF
CRS or RCS?

10. Subtypes Type I, acute CRS Type II, chronic CRS
Type III, acute renocardiac syndrome
Type IV, chronic renocardiac syndrome
Type V, secondary CRS -- sepsis, amyloidosis

11. Cardio-Renal Syndrome
CHF patients at increased risk for CRS:
Hypertension
Diabetes
Severe Vascular Disease
Elderly

12. Cardio-Renal Syndrome
Background
Pathophysiology
Management
Conclusions

13. Pathophysiology Neurohormonal Factors: SNS, RAAS, AVP System
Hemodynamics:
Loss of Cardiac Output
Transrenal perfusion pressure
Intrarenal hemodynamics

14. Neurohormonal Axis
Adenosine

15. CHF Hemodynamics Systolic or Diastolic CHF
Exacerbations -- Symptomatology seen objectively
Elevated PCWP
Elevations of INR, Alkaline Phosphatase
Elevations of Creatinine
Shift in paradigm

16. Damman, K. et al. J Am Coll Cardiol 2009;53:582-588
CVP and Renal Failure
2,557 patients underwent RHC
Age 59 ± 15 years
57% were men
Renal Function using estimated Glomerular Filtration Rate (eGFR)
Damman, K. et al. J Am Coll Cardiol 2009;53:

17. Damman, K. et al. J Am Coll Cardiol 2009;53:582-588
Curvilinear Relationship Between CVP and eGFR According to Different Cardiac Index Values
Solid line = cardiac index <2.5
dashed line = cardiac index 2.5 to 3.2
dotted line = cardiac index >3.2
p =
Central Venous Pressure
Damman, K. et al. J Am Coll Cardiol 2009;53:

18. Damman, K. et al. J Am Coll Cardiol 2009;53:582-588
CVP and Renal Failure
Kaplan-Meier Analysis of Event-Free Survival According to Tertiles of CVP
Damman, K. et al. J Am Coll Cardiol 2009;53:

19. Renal Hemodynamics Transrenal perfusion pressure TRPP = MAP - CVP
CVP influenced:
PAP -- Oxygenation, Valve Dysfunction, CO
Volume Status
MAP -- Perfusion Pressure
Cardiac Output
Systemic Vascular Resistance

20. Renal Hemodynamics
Ultimately lack of adequate transrenal perfusion pressure:
Renal Hypoxia
Inflammation / Cytokine Release
Progressive loss of nephron function and structural
Activation of the Neurohormonal cascade

21. Cardio-Renal Syndrome
Background
Pathophysiology
Management Options
Case

22. The Cardio-Renal Syndrome
Treatment Goals
Same goals as ADHF
Removal of Volume
Optimizing Hemodynamics
Complicated by chronic renal failure and acutely worsening renal function

23. Removal of Volume Loop Diuretics Brain Naturetic Peptide
Arginine Vasopressin Antatonism
Adenosine Antagonism
Ultrafiltration

24. Loop Diuretics Goal --> Deplete extracellular fluid volume
Balanced refilling interstitium to intravascular compartment
Reality --> Contraction of circulating volume > Activation of neurohormonal response

25. Loop Diuretics
Furosemide
Blockage of the thick ascending loop Na/ K/ 2 Cl pump
Acts intraluminally
Travels Bound to albumin
High Na delivered to distal tubules
Chronic use -> cellular hypertrophy -> increased Na reabsorption -> Failure of diuresis

26. Diuretic Resistance Inadequate dosing Cellular Hypertrophy
Bolus vs Continuous Infusion
Double Diuretic Therapy
Nutritionally Deficient Patients

27. Loop Diuretic Dosing Dose response curve is not smooth
Thus, no diruresis until threshold dose reached
If 20 mg IV once a day is insufficient; BID will be just as ineffective
Torsemide and Bumetanide vs Furosemide
Similar iv bioavailabiltiy
Improved Oral Bioavailablity

28. Braking Phenomenon Continuous Infusion Limited Data Cochrane Review
Short term tolerance after the first dose
Continuous Infusion
Limited Data
Cochrane Review
Improved safety
Improved diuresis
Shorter Hospital Stay
Lower Cardiac Mortality in a single study
Cochrane Database Syst Rev p. CD

29. The DOSE Trial Diuretic Optimization Strategies Evaluation
308 patients with ADHF
Low vs High Dose Furosemide
Continuous vs a12 hour dosing
Overall no significant difference among all groups
Patients symptoms
Creatinine
High Dose group had a greater diuresis with transient increases in creatinine
N Engl J Med Mar 3;364(9):

30. Double Diuretic Therapy or Sequential Nephron Blockade
Diuretic Resistance
Double Diuretic Therapy or Sequential Nephron Blockade
Loop + Thiazide
Chlorothiazide 250 mg vs 500 mg IV / Metolazone 5-10 mg PO
Very Effective -- Weight loss and edema resolution
Double Sodium Excretion
CAUTION: Hyponatremia, Hypotension, Worsening renal function
Chronic use -> cellular hypertrophy -> increased Na reabsorption -> Failure of diuresis
J Am Coll Cardiol, 2010; 56: , doi: /j.jacc

31. Diuretic Resistance **Addition of salt poor albumin**
Travels bound to albumin --> Delivered to Glomerulus --> Filtered --> Acts luminal side of thick ascending loop
Advanced CHF / Chronically ill
Elevated catecholamines (Catabolic)
Low serum albumin
Decreased delivery of diuretic to renal tubules
**Addition of salt poor albumin**
Furosemide-Albumin dimer allows better drug delivery
Clin Pharmacokinet May;18(5):

32. Brain Natriuretic Peptide
LV volume overload --> Cardiac Myocytes secrete BNP precursor --> Converted to proBNP --> ProBNP cleaved into:
C-terminal BNP (biologically active)
Decrease in SVR and CVP
Increase natriuresis
N-terminal BNP or NT-proBNP (biologically inactive)

33. Nesiritide (Natrecor)
New to market in 2001
Actions in ADHF
PCWP reduced within 15 minutes of administration
Resultant decreases in PA and RA pressure
Reduced SVRI
Resultant increase in CO
Enhances loop diuretic effects
Modest intrinsic natriuretic and diuretic effects
No tachyphylaxis
Blocks loop diuretic effects of aldosterone up- regulation
Cleve Clin J Med Mar;69(3): Review
Clin Cardiol Jun;33(6):330-6

34. ASCEND-HF Over 7000 patients with ADHF -- standard therapy
Nesiritide infusion 24 hrs - 7 days vs placebo
Primary End points:
CHF mortality and readmission (30 days)
Self reported Dyspnea at 6 and 24 hours

35. ASCEND-HF End points Placebo (%), n=3511 Nesiritide (%), n=3496 p
30-d death/HF hospitalization*
10.1
9.4
0.31
30-d death
4.0
3.6
30-d HF rehospitalization
6.1
6.0
Dyspnea at 6 h*
42.1
44.5
0.030
Moderately better
28.7
29.5
Markedly better
13.4
15.0
Dyspnea at 24 h*
66.1
68.2
0.007
38.6
37.8
27.5
30.4
>25% decrease eGFR
31.4
0.11

36. ASCEND-HF Role of Natrecor: Resolved Concerns: Worsening mortality
Worsening renal function
No significant benefit compared to standard therapy
Improved Dyspnea Score ($500.00/day)

37. Arginine Vasopressin
Arginine vasopressin (AVP), secreted by posterior pituitary
V1 Vascular receptor
V2 Renal receptor
Proportional to the severity of HF
Contributes to fluid retention and hyponatremia

38. Hyponatremia

39. ACTIV Trial Initial trial for Tolvaptan -- AVP antagonist
319 patients with systolic dysfunction (<40%) admitted with exacerbation
Tolvaptan vs Placebo/ Standard Treatment
Greater loss of body weight
Greater urine output at 24 hours
Increase in serum sodium
JAMA Apr 28;291(16):

40. EVEREST Trial
Efficacy of Vasopressin Antagonism in HF Outcome Study With Tolvaptan
Over 4000 patients in two separate study groups
EF < 40%
Tolvaptan (30mg) vs Placebo in combination with standard HF thearpy
Treatment time up to 7 days
JAMA Mar 28;297(12): Epub 2007 Mar 25

41. Tolvaptan Placebo Baseline Meds Diuretics 97.1 96.6 ACEi / ARB 84.3
% of patients
Placebo
(n=2061)
Baseline Meds
Diuretics
97.1
96.6
ACEi / ARB
84.3
84.1
β-blocker
70.8
69.6
Aldo blocker
53.6
54.7
IV inotrope
4.0
4.3
Nesiritide
4.2
5.1
Baseline HF Characteristics
Dyspnea
90.9
91.1
Edema
79.3
JVD ≥ 10 cm H2O
27.0
26.9
Serum Na+ <134 mEq/L
7.9
8.0

42. EVEREST Trial
JAMA Mar 28;297(12): Epub 2007 Mar 25

43. EVEREST Trial
JAMA Mar 28;297(12): Epub 2007 Mar 25

44. EVEREST Trial
JAMA Mar 28;297(12): Epub 2007 Mar 25

45. EVEREST Trial No change over 24 month follow up: All Cause Mortality
Cardiovascular Mortality
Heart Failure Hospitalization
JAMA Mar 28;297(12): Epub 2007 Mar 25

46. Adenosine?? Elevated levels seen in ADHF
Released locally in response to stress (Macula Densa) and sodium delivery to the DCT
Actions:
Afferent Arteriole Vasoconstriction
Decreased GFR
Sodium reabsorption
Tubuloglomerular feedback mechanism for regulation of GFR

47. Adenosine Tubuloglomerular Feedback
Acute delivery of sodium to the distal tubules (Lasix)
Adenosine further released from the macula densa
Further renal dysfunction
Br J Pharmacol August 2; 139(8): 1383–1388.

48. Adenosine Antagonism BG9719
63 patients with ADHF
Compared Groups
Lasix Alone
Adenosine Antagonist Alone
Combination thearpy
Circulation. 2002;105:

49. Adenosine
Circulation. 2002;105:

50. Ultrafiltration
The removal of isotonic volume across a semipermeable membrane
Hemodialysis -- Removal of volume and solutes using a concentration gradient
UF does not decrease sodium presentation to the macula densa
Avoids neurohormonally mediated sodium and water reabsorption

51. Ultrafiltration Advantages Low Flow Catheters -- Simple PICC line
Veno-Venous filtration
No ICU monitoring needed

52. UNLOAD Trial 200 Patients with ADHF Randomized:
Conventional IV Diuresis
UF up to 500cc/hr
Am Coll Cardiol Feb 13;49(6):

53. UNLOAD Trial Hypotension during 48 h after randomization:
Similar UF (4 of 100) 4% vs. Standard (3 of 100) 3%
Net fluid loss 48 h after randomization:
UF 4.6 ± 2.6 L
Standard-care 3.3 ± 2.6 L (p = 0.001)
Am Coll Cardiol Feb 13;49(6):

54. UNLOAD Trial
Am Coll Cardiol Feb 13;49(6):

55. UNLOAD Trial
Am Coll Cardiol Feb 13;49(6):

56. Clinical Presentation
68 y.o. man with iCMO admitted with volume overload consistent with CHF exacerbation
Diuresis poor
Creatinine Rising
Laboratory Studies
Sodium 132
Creatinine 1.8
Hemoglobin 9.8
Albumin 2.2

57. TRPP = MAP - CVP Goals: Improve symptoms
Limit further activation of the neurohormonal cascase
Little has been done to improve mortality
TRPP = MAP - CVP

58. Conclusions
The Cardio-Renal Syndrome is a worst case scenario for the CHF patient
Mortality is clearly worsened
Management is difficult:
Many options; nothing improves mortality
Promising new therapies -- Adenosine . . .
Each readmission for ADHF increases mortality thus optimization (Ultrafiltration) may play a larger role