Nephrology Mini-Symposium:

Acute Cardiorenal Syndrome

R3潘思宇 ,R3李宗育 ,R3張凱迪 ,R3柯雅琳R5王介立 /VS林水龍

Nov. 24th, 2010

“Cardiorenal” for 100 Years• Sir Thomas Lewis (1881-1945)

Lewis T., Br Med J 1913;2:1417-20

PubMed Trend

NIH Definition

Ronco Classification

Working Definition (2004)

At its extreme, cardio-renal dysregulation leads to what is

termed “cardio-renal syndrome” in which therapy to relieve congestive symptoms of heart failure is limited by further decline in renal function. It is clear that our current understanding of cardio-renal connections is inadequate to explain many of the clinical observations in heart failure or to direct its therapy.

NHLBI Working Group. http://www.nhlbi.nih.gov/meetings/workshops/cardiorenal-hf-hd.htm

Proposed Classification (2008)

Acute Chronic

HeartKidney

KidneyHeart

Ronco C. et al. J Am Coll Cardiol 2008;52:1527-39.

(cardiorenal)

(renocardiac)

Cardiorenal Syndrome is Always There

Type 2 and 4

Type 3

This year, 2010, we present you the…

Type 1 Cardiorenal Syndrome

Acute decompensated heart failure

Acute myocardial infarction

Low cardiac output syndrome post cardiac surgery

There’s Always a Problem…CASE

PRESENTATION

Acute Cardiorenal Syndrome

Epidemiology & Pathophysiology. R3 潘思宇Diagnosis & Management......…... R3 李宗育Volume & Diuretics………………. R3 張凱迪Ultrafiltration………………………. R3 柯雅琳

R5 王介立VS 林水龍

Cardiorenal Syndrome Type I

• Acute heart disorder leading to acute kidney injury

• Acute heart disorder ?– Acute decompensated heart failure– Acute coronary syndrome– (Low cardiac output syndrome after open heart surgery)

• Acute kidney injury ?– ARF, Worsening renal function– AKI: RIFLE, AKIN, K-DIGO– Biomarkers: NGAL, cystatin C

Epidemiology

Acute decompensated heart failure

Acute coronary syndrome

Acute decompensated heart failure

Observational, 2002/10~2004/10, FranceWRF:↑Cre > 0.3 mg/dL, Total: 416 with AHF

WRF: 37%WRF: 37%

D. Logeart et al, Int J Cardiol 2008; 127: 228–232

Event: death or unscheduled readmission for HF

P = 0.01P = 0.01

D. Logeart et al, Int J Cardiol 2008; 127: 228–232

Acute coronary syndrome

Observational, 1994/1~1996/2, Total: 147007 with AMIMild: ↑0.3~0.4, Mod: ↑0.5~0.9, Severe: ↑ 1.0 mg/dL≧

CR Parikh et al, Arch Intern Med. 2008;168(9):987-995

7.1%7.1% 7.1%7.1%

5.2%5.2%

Observational, 1994/1~1996/2, Total: 147007 with AMIMild: ↑0.3~0.4, Mod: ↑0.5~0.9, Severe: ↑ 1.0 mg/dL≧

P < 0.01P < 0.01At all time pointsAt all time points

CR Parikh et al, Arch Intern Med. 2008;168(9):987-9951 yr 10 yr5 yr3 yr

Pathophysiology

The low flow state hypothesis

Venous congestion: IAP & CVP

Others: Neurohormonal activation

JG Abuelo et al, N Engl J Med 2007; 357(8): 797-805

Pgc

PT

Pgc: Glomerular pressure, PT : Tubular pressure

πgc: Glomerular colloid p, πT : Tubular colloid p

△π

GFR GFR αα ( ( Pgc - PT - △π)

• Pgc

– MAP?– Intra-Abdominal hypertension?– Change of Resistance at A or E arteriole?

• PT

– Intra-Abdominal hypertension?– Tubular obstruction?

Factors affect GFRPPgcgc αα (MAP – IAP) (MAP – IAP)MAPMAP αα Pgc α α GRFGRF

Franklin H. Epstein et al, N Engl J Med 1999; 341(8): 577-585

If this low output theory holds true, then …

↓LVEF / CI ↓GFR

這病人 Kidney 不好

灌水 Dopamine !!!

↓Renal Renal perfusionperfusion??

Prospective, 1990, USA, CHF, Total: 34A: CI>2 ; B: CI 1.5~2 ; C: CI <1.5 L/min/m2

Ljungman et al. Drugs 1990; 39(Suppl. 4): 10-21

Autoregulation

Renal auto-regulation

Brenner and Rector’s The Kidney, 8th edhttp://www2.kumc.edu/ki/physiology/course/two/2_4.htm

• Pgc

– MAP?– Intra-Abdominal hypertension?– Change of Resistance at A or E arteriole?

• PT

– Intra-Abdominal hypertension?– Tubular obstruction?

Factors affect GFR

PPTT αα IAPIAP

PPgcgc αα (MAP – (MAP – IAPIAP))

Wilfried Mullens et at, Intensive Care Med (2006) 32:1722–1732

IAP range in critical careNormal: 5-7 mmHgElevated: ≥8 mmHg

IAH: ≥ 12mmHg

Prospective cohort, 2006/11~2007/5, CCU, USAAHF: LVEF<30%, PCWP>18 or CVP>8, Total: 40

Goal: PCWP<18, CVP<8, CI>2.2

Wilfried Mullens et at, Intensive Care Med (2006) 32:1722–1732

Retrospective cohort, 1989/1~2006/12, CCU, NetherlandPatient s/p Rt heart catheterization, Total: 2557

Baseline CVP vs. GFR

Kevin Damman et al., J Am Coll Cardiol 2009; 53(7): 582–8

Prospective, 2006/1~2007/6, USA, CCU, Total: 145Inclusion: LVEF<30%, CI<2.4, PCWP>18 or CVP>8

PA catheter goal: PCWP<18, CVP<8, & CI>2.4

Wilfried Mullens et al, J Am Coll Cardiol 2009; 53(7) 589–96

CVP rather than CI ?

Animal study, Dog, 1931, Renal a & v cannulation

F. R. Winton et al, J Physiol 1931; 72: 49–61.

Fluid status evaluation in CRS

Venous congestion may be more important than hypovolemia

脫水 灌水 ??

Other postulated mechanisms of CRS

• Low evidence & inconclusive– Sympathetic overactivity– Adenosine– Vasopressin– Natriuretic peptide– Oxidative injury & endothelial dysfunction

Jeremy S. Bock et al, Circulation. 2010;121:2592-2600.

Sympathetic Overactivity

Gerald F. Dibona et al, Physiol Rev, 1997; 77(1): 75-197

Animal study, Rat, 1980, Renal sympathetic stimulate, Total: 10

Prospective cohort, 2007/6~2008/11, Australia & EuropeanHypertension s/p renal sympathetic denervation, Total: 45

Henry Krum et al, Lancet 2009; 373: 1275–81

Improvement of hypertension

Improvement of renal function??

Pathology

老師 , 第三床 ARF 咧要不要作 Renal biopsy 看一看 ?

第三床不是 第三床不是 Heart failureHeart failure 嗎嗎 ??阿就是阿就是 Pre-renal ARFPre-renal ARF 阿阿 , Biopsy, Biopsy 做什做什

麼麼 ??

Pathology

• Acute heart failure not a traditional indication for renal biopsy

• Case report– The characteristics of acute renal failure in

cardiogenic shock in the elderly– 4 patients with cardiogenic shock and ARF– 1 patient with ATN– 3 patients without pathological change

Durakovi et al, ZFA 1986; 41(5): 301-5

Can we predict who will developed CRS in patients presented with acute cardiac dysfunction?

Known Predictors from Past Observations (I)

WH Tang & W. Mullens. Heart. 2010; 96(4):255-60

Known Predictors from Past Observations (II)

WH Tang & W. Mullens. Heart. 2010; 96(4):255-60

Summary• AKI occurs frequently in AHF (type 1 CRS)

– It is an independent risk factor of worse outcome– However, only very limited prospective

observational studies have addressed the issues

• The mechanism of type 1 CRS remained largely speculative– We have no ideas why his (her) kidney failed– Venous congestion should be kept in mind other

than arterial underfilling

Acute Cardiorenal Syndrome

Epidemiology & Pathophysiology. R3 潘思宇Diagnosis & Management......…... R3 李宗育Volume & Diuretics………………. R3 張凱迪Ultrafiltration………………………. R3 柯雅琳

R5 王介立VS 林水龍

DIAGNOSIS

Back to the Problem…CASE

PRESENTATION

How do we know the sequence?

Time Course of the eGFR

Acute (type 1,3) rather than chronic (type 2,4)…

CASEPRESENTATION

CKD stage 3

AKI

Cause of CKD?CASE

PRESENTATION

12 cm

(Long-standing; microscopicovert)

Other non-DM cause of CKD related to CVD: - Ischemic nephropathy (renovascular disease)

- Malignant hypertension

AKI from Heart?CASE

PRESENTATION

Hypotensive episode?

“No diagnostic criteria = by exclusion”

Typical Acute CRS• Acute heart failure syndrome

• Acute kidney injury

• No evidence of intrinsic kidney disease other than the baseline CKD

So far, has the diagnosis of type 1 cardiorenal syndrome been secured?

Mimickers of Type 1 CRS• NSAIDs causing concurrent heart failure

and vasomotor nephropathy

• Flash pulmonary edema (bilateral renal artery stenosis)

• Hypertensive crisis from identifiable causes (e.g. pheochromocytoma)

(the primary cause is outside the heart)(potentially treatable)

BEDSIDE APPROACH

Bedside Evaluation

Evaluation of perfusion & congestion is equally important in acute renal failure

1Nohria A, et, al. JAMA 2002;287:628-40

MANAGEMENT

Treatment of Type 1 CRS

: Not mentioned

: Not mentioned (unpublished draft)

&

Heart failure guideline

AKI guideline

Overview

ADHF AKI Acute CRS

Drug Therapy …

CPAP ?

Ultrafiltration

Drug Therapy for Acute CRS• Traditional agents for AHF

– Oxygen– Morphine– Vasodilators– Inotropopic agents– Vasopressin antagonists– Loop diuretics

• Investigational agents with specific renal effect

Renal effect?

Vasodilator therapy

• Nitroglycerin– Effect on Renal Function ?

Lagrand WK, et al. Curr Probl Cardiol. 2009;34(8):330-349.

• Sodium nitroprusside– Improved outcomes and stable kidney function

• Nesiritide– Synthetic human B type natriuretic peptide:

potent vasodilator– Increased the risk of worsening renal function ?

Vasodilator therapy

Mullens W, et al. J Am Coll Cardiol. 2008;52(3):200-207.

Sackner-Bernstein JD, et al. Circulation 2005; 111: 1487-1491

Comparison between clinical effects of intravenous vasodilators in the treatment of heart failure

Elkayam, U., M. Janmohamed, et al. (2008). "Vasodilators in the management of acute heart failure." Crit Care Med 36(1 Suppl): S95-105.

Elkayam, U., et al. (2008). Crit Care Med 36(1 Suppl): S95-105

Variables Nitroprusside Nitroglycerine Nesiritide

Clinical studies -- + +++

Hemodynamic effect +++ +++ +++

Tolerance -- ++ --

Need for dose titration

+++ +++ --

Effect on coronary flow Myocardial ischemia NAEffect of urine output NA NA +/-Effect on neurohormones

+ + +

Mullens W, et al. J Am Coll Cardiol. 2008;52(3):200-207.

Sodium nitroprusside for advanced low-output heart failure. retrospective, 2000~2005, USA, ADHF: CI<2

L/min/m2,Total: 175, Scre: 1.3~1.5 mg/dL

Sackner-Bernstein JD., et al. Circulation 2005; 111: 1487-1491

The use of nesiritide for ADHF did not avoid type 1 CRS and increased the risk of worsening kidney function, as well as mortality, in the active treatment groups

Incidence of Worsening Renal Function in studies ofNesiritide for ADHF. Meta-analysis of 5 randomized double-blind controlled trials , WRF: SCre > 0.5mg/dL, USA, Total: 1269

Witteles RM, et al. J Am Coll Cardiol. 2007 Nov 6;50(19):1835-40.

No significant difference was observed in the primary end point of worsenedrenal function (increase in serum creatinine 20%)

Impact of Nesiritide on renal function. Separate randomized double-blind controlled trials , Scre: 1.82: 1.86mg/dL, USA, Total: 75

Inotropic Agent: Levosimendan

• Lusitropic activity(calcium sensitizer) Improves hemodynamics and renal perfusion compared with dobutamine but not comfirmed in SURVIVE study

Yilmaz MB, et al. Cardiovasc Drugs Ther. 2007;21(6):431-435.

Levosimendan: Improves hemodynamics and renal perfusion

Yilmaz MB, et al. Cardiovasc Drugs Ther. 2007;21(6):431-435.

P< 0.001

P= 0.008

P< 0.001

P > 0.05 for all

Mebazaa A. et al,. SURVIVE Investigators. JAMA. 297(17):1883-91, 2007 May 2.

Levosimendan Dobutamine

Cox Proportional Hazards P = 0.04

Time Since Start of Study Drug Infusion, d

Effect of Dobutamine and Levosimendan Treatment on All-Cause Mortality -- The SURVIVE Trial: randomized, double-blind trial, 2003~2004, LVEF: 24%,Total: 1327, Scre: >2.5 mg/Dl(n=87)

0 30 60 90 120 150 180

1.0

0.8

0.6

0.4

0.2

0

Kellum JA, et al. Crit. Care Med 2001;29: 1526-1531

The use of low-dose dopamine for the treatment or prevention of acute renal failure cannot be justified on the basis of available evidence and should be eliminated from routineclinical use.

Vasopressin Receptor Antagonist

• Increased renal free water clearance and improvement in hyponatremia and weight loss without survival benefit

Konstam MA, et al. the EVEREST Outcome Trial. JAMA 2007; 297: 1319-1331

Vasopressin Receptor Antagonist

Sanghi P, et al .Eur Heart J 2005;26:538-43.

Atrial underfilling

BaroreceptorsLeft atriumCarotid sinusAortic arch

Hyperosmolality

Osmoreceptors

Vascular smooth muscleV1 a receptors

Collecting duct of kidneyV2 receptors

Vasocontriction Water re-absorption

Profile of AVP receptor antagonists

Cleve Clin J Med. 2006 Sep;73 Suppl 3:S24-33.

Conivaptan (YM-087)

Tolvaptan(OPC-41061)

Receptor(s) V1A/ V2 V2

Admin. route Intravenous Oral

Urine volume

Urine Osmolality

Sodium excretion in 24hours

Acute hemodynamic effects of conivaptan

Udelson JE, et al. Circulation 2001;104:2417-23.

Placebo 10 mg 20 mg Conivaptan 40 mg

Time (h)

0 1 2 3 4 5 6 7 8 9 10 11 12

300

100

50

0

-50

-100

250

200

150

Konstam MA, et al.JAMA 2007; 297: 1319-1331

Log-Pank Test: P = 0.76Peto-Peto-Wilcoxaon Test: P = 0.68Stratified Peto-Peto-Wilcoxon Test: P= 0.68

All Cause Motality

Months of Study

All-Cause Mortality and Cardiovascular Mortality or Hospitalization —Tolvaptan (The EVEREST Outcome Trial): randomized, double-blind trial, 2003~2006, LVEF: 27.5%,Total: 4133, Scre: >1.3 mg/dl(n=827)

0 3 6 9 12 15 18 21 24

1.0

0.9

0.8

0.7

0.6

0.5 0.4 0.3

0.2

0.1

0

Investigational agents: Adenosine A1−Receptor Antagonist

Renal effects of Adenosine A1 receptor Antagonists in Congestive heart failure

Gottlieb SS. Drugs 2001;61:1387-93.

Tubule LumenIncreased NaCl delivery Increased adenosine (perhaps

from ATP needed for active transport)

Adenosine A1 receptor

Vasocontriction

Afferent arteriole

Adenosine A1 receptor AntagonistBG 9719KW3902 (Rolofylline)

Adenosine Antagonistgs

Stephen S. Gottlieb, Circulation. 2002;105:1348-1353

BG9719 + Furosemide

BG9719

Urine Volume (ml)0~8 hours(Day 1 - Baseline

BG9719 Dose (mcg/ml)-0.5 0 0.5 1 1.5 2 2,5 3

2000

1500

1000

500

0

Adenosine Antagonistgs

Stephen S. Gottlieb, Circulation. 2002;105:1348-1353

GFR(% change)(1~8 hours)

Urine Output (ml)(0~8 hours, Day 1 - Baseline)

BG9719

PlaceboFurosemide Alone

BG9719 + Furosemide

0 500 1000 1500 2000 2500

15

5

-5

-15

-25

Barry M. Massie, et al. N Engl J Med 2010; 363:1419-1428

Placebo

Rolofylline

Hazard ration: 1.03 (95% CI, 0.82-1.28)P = 0.82

Day

Rolofylline (KW3902), an Adenosine A1 receptor antagonist in acute heart failure with impaired renal function (PROTECT-1): randomized, double-blind trial, LVEF: 32%,Total: 2033, Ccr: 50.4~51 ml/min

0 30 60 90 120 150 180

35

30

25

20

15

10

5

0

Major Ongoing Clinical Trials of Renal-Sparing Treatment Strategies

Drug Trial acronym Phase Sample size

Natriuretic peptides Nesiritide

CD-NPASCEND-HF

CONDITION-HFIVII

7000380

Vasopression receptor antagonist Tolvaptan Conivaptan Lixivaptan

EVERESTCONVERT-HF

BALANCE

IIIIIIIII

3600105650

Adenosine A1 receptor antagonists Rolofylline SLV320 BG-9928

PROECT1&2RENO-DEFEND 1

POSEIDON/TRIDENT

IIIII

II/III

2000500

300/900

Standard treatment Loop diuretics Ultrafiltration

DOSE-AHFCARRESS

IVIV

300200

Summary• There is nothing specific for the diagnosis

of acute cardiorenal syndrome– Follow the principle of diagnosis of AKI

• No definite pharmacological therapy could be recommended for the acute cardiorenal syndrome– Follow the principle of therapy of AHF

Acute Cardiorenal Syndrome

Epidemiology & Pathophysiology. R3 潘思宇Diagnosis & Management......…... R3 李宗育Volume & Diuretics………………. R3 張凱迪Ultrafiltration………………………. R3 柯雅琳

R5 王介立VS 林水龍

How to Measure the Fluid Status?

Possible Methods to Evaluate Fluid Status

• History and Physical Examination• Body Weight• JVP/CVP/PCWP• Pulse wave variation• Urine Sodium• Natriuretic peptide• CXR• Thoracic Ultrasound• Vena Cava Ultrasound• Initial Distribution Volume of Glucose• Bioimpedance spectrography• ……

In our daily practice……

Toshiba.com

Library and Archives Canada

Wang CS, JAMA 2005;294:1944-1956

Evaluation about fluid status: History takingMeta-analysis of 18 studies during 1966~2005

FindingFinding SensitivitySensitivity SpecificitySpecificity Positive Positive LRLR

Negative Negative LRLR

Symptoms

Paroxysmal nocturnal dyspnea 0.41 0.84 2.6 0.70

Orthopnea 0.50 0.77 2.2 0.65

Edema 0.51 0.76 2.1 0.64

Dyspnea on exertion 0.84 0.34 1.3 0.48

Fatigue and weight gain 0.31 0.70 1.0 0.99

Cough 0.36 0.61 0.93 1.0

FindingFinding SensitivitySensitivity SpecificitySpecificity Positive Positive LRLR

Negative Negative LRLR

Physical examinationThird heart sound 0.13 0.99 11 0.88

Abdominal jugular reflux 0.24 0.96 6.1 0.79

Jugular vein engorgement 0.39 0.92 5.1 0.66

Rales 0.66 0.78 2.8 0.51

Any murmur 0.27 0.90 2.6 0.81

Lower extremit edema 0.50 0.78 2.3 0.64

SBP<100mmHg 0.06 0.97 2.0 0.97

Fourth heart sound 0.05 0.97 1.6 0.98

SBP>150 0.28 0.73 1.0 0.99

Wheezing 0.22 0.58 0.52 1.3

Ascites 0.01 0.97 0.33 1.0

Wang CS, JAMA 2005;294:1944-1956

Evaluation about fluid status: Physical examinationMeta-analysis of 18 studies during 1966~2005

Body Weight

Chaudhry SI, et al, Circulation 2007;116:1549–1554

Days before admission

Chest Radiography

10 ± 4 22 ± 4 34 ± 4

Cardiomegaly 87 98 100

Redistribution 26 40 66

Interstitial edema 16 47 61

Peribronchial cuffing 10 40 22

Hilar haziness 16 40 44

Kerley B line 16 40 39Chakko S, et al, Am J Med 1991;90:353–359

PCWPCXR finding (%)

Chest Radiography and Diagnosis of CHF

Acute Decompensated Heart Failure National Registry (ADHERE)

(~2004/7)

Patients discharge with diagnosis of CHF

Sean P. Collins et.al, Ann Emerg Med. 2006;47:13-18

**CXR negative rate: 18.7%

Chest Radiography

Limitation

• Technique

• Abnormalities lag the clinical appearance by hours

• Unreliable sensitivity, specificity and predictive value in Chronic HF patients

Natriuretic Peptides

• BNP

• NT-pro-BNP

Marc Vanderheyden, et al, J. Am. Coll. Cardiol. 2004;44;2349-2354

NP level: Rapid Response to ↓PCWP

Kazanegra R, et al. J Card Fail 2001;7:21–29

Why NP Level did not Decline Despite Effective Treatment?

1. Acute cardiorenal syndrome renal insufficiency

2. Mobilization of third-space fluid rather than lowering cardiac filling pressure

3. High optivolemic BNP level

Maisel A , et al, Eur J Heart Fail, 2008;10:824-39

NP level: “Wet” versus “Optivolaemic”BNPpg/mL

t

Wet BNP levels

Optivolemic (dry) BNP levels

DecongestionDecongestionDecongestionDecongestion

Maisel A , et al, Eur J Heart Fail, 2008;10:824-39

?

Thoracic Ultrasound

• B-lines: – thickened interstitia – fluid-filled alveoli

Thoracic Ultrasound

Liteplo AS. et al, Acad Emerg Med, 2009;16:201-210

Threshold for a Positive Test Sensitivity Specificity LR+ LR-

8-zone Totally positive (4-B) 0.23 1.00 Infinite 0.78

8-zone Positive (> 2-B) 0.58 0.85 3.88 0.50

2-Zone (4 and 8) 0.53 0.89 4.73 0.53

Thoracic Ultrasound

Positive ultrasound lung scans in the 11 individualizeable thoracic areas before and after treatment in 70 ADHF patients

Thoracic area Before tx After tx P

Giovanni Volpicelli, et.al, Am J Emerg Med, 2008;26:585-591

• Predicting right atriam pressure > 10mmHg

IVC Respiratory Variation Ultrasound

%Collapse % sen. % spe.

20 38 100

40 74 91

50 87 82

60 94 44

80 98 14

Kircher B, et al, J,Am J Cardiol. 1990;66(4):493-496

IVC Respiratory Variation Ultrasound

IVC Respiratory Variation:

• CHF: 9.6% vs non-CHF: 46%

David J. Blehar, et.al, Am J Emerg Med, 2009; 27: 71-75

1

0.4

0.8

0.6

0.2

0.2

1-specificity0.80.60.4

Sens

itivi

ty

**Cutoff value: 15% -Sensitivity: 93% -Specificity: 84%

Initial Distribution Volume of Glucose

•  

Gabbanelli V, et.al, Intensive care medicine 2004;30:2067-73.

Bioimpedance Spectroscopy

Calculate the proportion of total body water, fat, and muscle

Limitation:1. Only validated in chronic HD patients

2. Interfere by other body monitor

Wabel P, et al. Nephrol Dial Transplant 2008;23:2965-71

SummaryMeasurements Advantages Limitations

History and Physical Examination Rapid assessment Low sensitivities

Body WeightSimple measurement May not represent intravacular

volume change

JVP/CVP/PCWP Good sensitivity and specificity Need invasive method

Pulse wave variation Rapid assessment Invasive arterial cannulation

Natriuretic peptidePredict outcomes Less specificity in certain

conditions (CKD, obesity…)

CXRObjectively represent pulmonary congestion

Not enough sensitive or specific

Thoracic UltrasoundRapid and easy to use at bedside.

Evolving technology; requires training

Vena Cava UltrasoundRapid and easy to use at bedside

Evolving technology; requires training

Initial Distribution Volume of Glucose

Rapid and easy to use at bedside

Cannot represent extravascular volume

Bioimpedance spectrographyNeed specialized equipment Evolving technology; may not

represent preload

Gheorghiade M, et al. European Journal of Heart Failure 2010;12:423-33.