Cardiorenal syndrome Chaken 2017

1. CARDIORENAL SYNDROME
Maj. Chaken Maniyan
Fellow Nephrology
Phramongkutklao hospital

2. Cardiorenal syndrome
§ Each dysfunctional organ has the ability to initiate
and perpetuate disease in the other organ through
common haemodynamic, neurohormonal, and
immunological and/or biochemical feedback
pathways
Braam, B. et al. Nat. Rev. Nephrol. 10, 48–55 (2014);

3. Importance of CRS
§ Prevalence of moderate to severe kidney
impairment (GFR <60 mL/min per1.73 m2) is
30 to 60 percent in patients with HF
§ Mortality increased by 15 % for every 10 mL/min
reduction in estimated GFR
1.Krumholz HM, ChenYT,VaccarinoV, et al..Am J Cardiol 2000; 85:1110.

4. Renal dysfunction and CV outcome

5. Outcome of HF with 1 year death
Worst outcome when congestion with WRF
Metra M., Davison B., Bettari L., et al: Circ Heart Fail 2012; 5: pp. 54-62

6. CRS type 1 (Acute Carido-Renal)
C Ronco et al. JACC Vol. 52, No. 19, 2008 November 4, 2008:1527–39
Acute valvular disease

7. Impact of venous congestion on
glomerular filtration pressure
M. Jessup et al , JACCVol. 53, No. 7, 2009The Cardiorenal Syndrome February 17, 2009:597–9

8. CRS type 2 (Chronic Cardiorenal)
C Ronco et al. JACC Vol. 52, No. 19, 2008 November 4, 2008:1527–39

9. CRS type 3 (Acute Renocardiac)
C Ronco et al. JACC Vol. 52, No. 19, 2008 November 4, 2008:1527–39

10. CRS type 4 (Chronic Renocardiac)
C Ronco et al. JACC Vol. 52, No. 19, 2008 November 4, 2008:1527–39

11. CRS type 5 (systemic involvement )
C Ronco et al. JACC Vol. 52, No. 19, 2008 November 4, 2008:1527–39

12. Prevention and Treatment of
Cardiorenal Syndromes
§ Pathophysiology of CRS is complex, multimodality
preventive strategies needed
§ Basic preventive strategies
§ Blood pressure control
§ Use of drugs that block RAAS
§ β-adrenergic blockers
§ Modification of coronary artery disease risk factors
Brenner & Rector’sThe Kidney 9th Edition

13. Prevention and Treatment of
Cardiorenal Syndromes
§ Chronic type II CRS
§ ACE inhibitors, angiotensin receptor blockers
§ β-adrenergic blockers
§ Aldosterone receptor blockers
§ Combination of nitrates and hydralazine, and cardiac
resynchronization therapy
§ Optimal management of sodium and extracellular fluid
volume through consumption of a low-sodium diet and
use of diuretics
Brenner & Rector’sThe Kidney 9th Edition

14. Prevention and Treatment of
Cardiorenal Syndromes
§ Type III renocardiac syndrome
§ the clinical problem is often sodium and water retention.
Avoidance of hypervolemia may help preventing cardiac
decompensation
§ Uremic abnormalities and hyperkalemia may further
contribute to secondary heart dysfunction
Brenner & Rector’sThe Kidney 9th Edition

15. Prevention and Treatment of
Cardiorenal Syndromes
§ Type IV renocardiac syndrome
§ involves accelerated calcific atherosclerosis, progressive
left ventricular hypertrophy, and the development of
diastolic and systolic dysfunction in patients with CKD
§ The core prevention concept is that the reduction in the
rate of progression of CKD may result in
cardioprotection
Brenner & Rector’sThe Kidney 9th Edition

16. Prevention and Treatment of
Cardiorenal Syndromes
§ TypeV CRS
§ treatment of the primary illness (diabetes mellitus,
amyloidosis, sepsis, rhabdomyolysis, hemorrhagic shock, etc.)
in general improves both heart and kidney function.
Brenner & Rector’sThe Kidney 9th Edition

17. Diagnostic algorithm for a
diagnosis of heart failure
2016 ESC Guidelines

19. Treatment algorithm for a
diagnosis of heart failure
2016 ESC Guidelines

22. Diuretic Resistance
er Maaten J.M. et al Nat Rev Cardiol 2015; 12: pp. 184-192

23. Proposed definitions of diuretic resistance
§ Persistent congestion, despite adequate and
escalating doses of diuretic equivalent to ≥80
mg/day furosemide;
§ FeNa< 0.2%
§ Na excretion < 90 mEq within 72 h of 160-mg
twice-daily dose of furosemide.
er Maaten J.M. et al Nat Rev Cardiol 2015; 12: pp. 184-192

25. DOSE TRIAL design
Felker et al. NEJM 2011;364:797

27. Symptoms Relief (VAS)
Felker et al. NEJM 2011;364:797

28. DOSE Study
Change in serum Cr over 60d
Felker et al. NEJM 2011;364:797

29. Secondary outcome

30. Principle of ultrafiltration
(hemofiltration)

31. Contemporary Ultrafiltration Devices
Aquadex System 100 Bellco Dedyca CHIARA
Location of venous access Central or peripheral venous access Central or peripheral venous Central or peripheral
venous access
Continuous vs. Batch blood
withdrawal and return
Continuous Batch (single needle)
Blood flow, mL/min
(min, max, nominal)
(10,100,40) (0,100,) (10,200,40)
Filter size (m2) 0.12
Volume of extracorporeal
circuit (mL)
33 <100 ~55
Rate of UF removal,
ml/hour (minimum,
maximum)
0-500 0-1000 60-500
Anti-coagulation 10-20 units/kg of heparin given IV,
single dose
A heparin pump provides
accurate continuous
anticoagulation
10-20 units/kg of heparin given
IV, single dose
Maximum treatment time,
hours
8 48 48

32. Simplified UF devices
§ Small size, portability
§ Low blood flow rates
§ Extracorporeal blood volume below 50 ml.

33. UF system
Maria Rosa Costanzo MD et al , JACC , 2017,Volume 69, Issue 19, Pages 2428-2445

34. Comparative Characteristics of
Loop Diuretic and Isolated UF
Loop Diuretic Agents Isolated UF
Direct neurohormonal activation No neurohormonal activation
Remove of hypotonic urine Removal of isotonic plasma water
Unpredictable elimination of sodium and
water
Precise control of rate and amount of fluid
removal
Development of diuretic agent resistance
with prolonged administration
Restoration of diuretic agent responsiveness
Risk of hypokalemia and hypomagnesemia No effect on plasma concentration of
potassium and magnesium
Peripheral venous access Peripheral or central venous catheter
No need for anticoagulation Need for anticoagulation
No extracorporeal circuit Need for extracorporeal circuit
Maria Rosa Costanzo MD et al , JACC , 2017,Volume 69, Issue 19, Pages 2428-2445

35. Pilot study : The SAFE
(Simple Access Fluid Extraction) trial
§ 21 congested patients with heart failure,
§ Non Randomized
§ Removal of average of 2.6 l of UF during 8-h session
§ No change in Scr, electrolyte , Hct , HR, SBP
§ No serious adverse event
Jaski B.E., Ha Jet al . J Card Fail 2003; 9: pp. 227-231

37. RAPID-CHF, 2005
N = 40
Hospitalized with HF, 2+ edema and ≥1 additional
sign of congestion
Single, 8-h course, median duration 8 h, median
volume removed 3,213 ml
Standard HF therapies determined by treating
physician
Weight loss 24 h post-consent
Index length of stay
Volume removal 24 h after consent
Primary outcome Secondary outcome
Adapted from Bart B.A., Boyle A., Bank A.J., et al, J Am Coll Cardiol 2005; 46: pp. 2043-2046

38. Median weight loss at 24 and 48 h
§ UF
§ Usual care
Bart B.A., Boyle A., Bank A.J., et al, J Am Coll Cardiol 2005; 46: pp. 2043-2046
RAPID-CHF, 2005

39. Median cumulative fluid removal
at 24 and 48 h
§ UF
§ Usual care
Bart B.A., Boyle A., Bank A.J., et al, J Am Coll Cardiol 2005; 46: pp. 2043-2046
RAPID-CHF, 2005

40. Secondary outcome RAPID-CHF
§ Index length of stay:
§ 6 days (UF) vs. 5 days (standard care); p = NS
§ Volume removal 24 h after consent:
§ 4,650 ml (UF) vs. 1,838 ml (standard care), p = 0.001
§ 1 catheter site infection (UF)
Bart B.A., Boyle A., Bank A.J., et al, J Am Coll Cardiol 2005; 46: pp. 2043-2046

42. UNLOAD, 2007
Hospitalized with HF, 2+ N = 200
Hospitalized with HF, ≥2 signs of fluid overload and ≥1 additional
sign of congestion
Aquadex System 100†
Mean fluid removal rate 241 ml/h for 12.3 ± 12 h
Standard care: IV diuretic agents. For each 24-h
period, at least twice the pre-hospitalization daily
oral dose
Weight loss and dyspnea assessment at
48 h after randomization
Index length of stay
Volume 90 days: HF rehospitalization:
Unscheduled clinic/emergency visits:
Primary outcome Secondary outcome
Adapted from Costanzo M.R.,., et al. J Am Coll Cardiol 2007; 49: pp. 675-683

43. Primary Outcome in UNLOAD, 2007
Significant improvement in
Weight loss and dyspnea score
at 48 hr
Costanzo M.R.,., et al. J Am Coll Cardiol 2007; 49: pp. 675-683

44. Significant less
rehospitalization from HF
within 90 days after
discharge
Secondary Outcome in UNLOAD, 2007
No significant between-group differences, except bleeding (1 UF vs. 7 standard, p = 0.032).
UF group: 1 catheter infection, 5 filter clotting events
Costanzo M.R.,., et al. J Am Coll Cardiol 2007; 49: pp. 675-683

47. CARRESS-HF, 2012
N = 188
Hospitalized with HF, ≥2 signs of congestion, and
recent ≥0.3 mg/dl sCr increase
Aquadex System 100 †at a fixed rate of 200 ml/h
Median duration 40 h
SPT with intravenous diuretic agents dosed to
maintain urine output 3–5 l/day
Mean sCr change:
Mean weight loss:
7 d: death, worsening HF, hemodialysis
60 d : HF hospitalization
Primary outcome Secondary outcome
Adapted from Bart B.A., et al: N Engl J Med 2012; 367: pp. 2296-2304

48. Bart B.A., et al: N Engl J Med 2012; 367: pp. 2296-2304
Primary Outcome in CARRESS-HF, 2012

49. Bart B.A., et al: N Engl J Med 2012; 367: pp. 2296-2304
Primary Outcome in CARRESS-HF, 2012

50. § At 7 days:
§ no difference in
§ death
§ worsening or persistent HF,
§ hemodialysis, SAE
§ At 60 days no difference in HF hospitalization (26%)
§ 60-day SAE:
72% UF vs. 57% SPT; p = 0.03,
§ (renal failure, bleeding, or catheter complications)
Secondary Outcome in CARRESS-HF, 2012
Bart B.A., et al: N Engl J Med 2012; 367: pp. 2296-2304

52. CUORE, 2014
N = 56
NYHA III or IV, LVEF ≤40%, ≥4 kg weight gain from
peripheral fluid overload, over 2 months
Dedyca device‡
Mean treatment duration 19 ± 90 h; volume
removed 4,254 ± 4,842 m
Intravenous diuretic agents according to guideline
recommendations
HF rehospitalization at 1 yr
Length of index hospitalization
Combined death or HF rehospitalization
Primary outcome Secondary outcome

53. Primary Outcome in CUORE, 2014
§ Freedom from rehospitalization for congestive heart
failure at 1 year in patients treated with ultrafiltration
Marenzi G., et al J Card Fail 2014; 20: pp. 9-17

54. Secondary Outcome in CUORE, 2014
Marenzi G., et al J Card Fail 2014; 20: pp. 9-17
§ Freedom from combined end point of rehospitalization for
CHF and death at 1 year

55. Secondary Outcome in CUORE, 2014
Marenzi G., et al J Card Fail 2014; 20: pp. 9-17
§ Length of hospitalization:
§ 7.4 (UF) vs. 9.1 days (standard care), p = 0.23
§ Premature clotting of filter in 6 patients
§ Mortality rate 1 yr:
7 (26%) UF vs. 11 (38%) standard care; p = 0.33

57. AVOID-HF, 2016
N = 224
Hospitalized with HF; ≥2 criteria for fluid overload;
receiving daily oral loop diuretic agents
AUF with Aquadex FlexFlow SystemMean fluid
removal rate 138 ± 47 ml/h for 80 ± 53 h
Adjusted loop diuretics
Mean furosemide-equivalent dose 271.26 ± 263.06 mg for
100 ± 78 h
Time to first HF event
(HF readmit or unscheduled outpatient
or treatment with iv loop diuretic or
UF)in 90 days
Length of index hospitalization:
30-day HF rehospitalizations/days
30-day CV rehospitalizations/days
Primary outcome Secondary outcome
Adapted from Costanzo M.R., et al:. J Am Coll Cardiol HF 2016; 4: pp. 95-105

58. Primary outcome AVOID-HF, 2016
Adapted from Costanzo M.R., et al:. J Am Coll Cardiol HF 2016; 4: pp. 95-105
Time to Heart Failure Event after Discharge

59. Secondary outcome AVOID-HF, 2016
Adapted from Costanzo M.R., et al:. J Am Coll Cardiol HF 2016; 4: pp. 95-105
§ Length of stay : 6 (AUF) vs. 5 (ALD) days, p = 0.106
§ 30-day HF rehosp./days at risk:
§ 11 of 2,876 (AUF) vs. 24 of 2,882 (ALD), p = 0.06
§ 30-day CV rehospitalizations/days at risk:
§ 17 of 2,882 (AUF) vs. 33 of 2,891 (ALD); p = 0.037
§ 90 days mortality rate 15% AUF vs. 13% ALD, p = 0.83

60. Ultrafiltration
2016 ESC Guidelines for management of Heart Failure

61. Marvin A. Et al , JAMA. 2007;297:1319-1331

62. EVEREST OUTCOME TRIAL 2007
N=4,133
Hospitalization for HF <48hrs, LVEF ≤40%
Fluid overload; Exclude Cr > 3.5
Tolvaptan (n=2,072) for 60 days Placebo (n=2,061)
All-cause mortality
CV death or rehospitalization
Length of index hospitalization:
30-day HF rehospitalizations/days
30-day CV rehospitalizations/days
Primary outcome Secondary outcome
Adapted from Marvin A. Et al , JAMA. 2007;297:1319-1331

63. Primary outcome
EVEREST OUTCOME TRIAL

64. EVEREST OUTCOME TRIAL conclusion
§ Early and sustained weight reduction -
Improvement in dyspnea (d1) and edema (d7)
§ No effect on global clinical status (VAS) at d7/DC
§ Normalization of serum Na in hyponatremic pts
§ No WRF
§ Long-term use had no effect on long-term
mortality or HF morbidity
Marvin A. Et al , JAMA. 2007;297:1319-1331

65. Systematic review of Tolvaptan use
Hauptman J J Cardiac Fail 2013;19:390e397

66. AVP antagonist in ADHF

67. EECP treatment on cardiac patients

68. § Based on principle of diastolic augmentation to increase
coronary flow while simultaneously decreasing systolic
afterload
§ During diastole, cuffs inflate sequentially from the calves
proximally to raise diastolic aortic pressure and
theoretically increase coronary perfusion pressure
§ At the same time, increased venous return would result in
increased cardiac output by Starling mechanism
§ Then the cuffs are rapidly decompressed at the onset of
systole creating negative pressure that decreases cardiac
afterload
EECP treatment on cardiac patients

71. Take Home
§ CRS is a pathophysiological condition.
§ Treatment is to be individualized based on etiology
§ Early diagnosis is important for better survival
§ Early novel biomarkers are to be used in diagnosis
§ Each patient with either CKD,CVD to be assessed with
risk factors and followed up