THE HEARTBREAK KID, NÉ

An age-old tragedy in two parts

Dr Malcolm Davies

Division of Nephrology, Charlotte Maxeke Johannebsurg Academic Hospital

21%

18%

11%11%

6% 6% 6% 6% 5%4% 3%

2% 1% 1%

ICU

Car

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Res

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Gen

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Gas

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Uro

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Car

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Vas

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End

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Orth

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Plastic S

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ry0

5

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March – September 2013

n = 156Incidence of AKI* in heart failure:

• Forman (n = 1004): 27%

• Krumholz (n = 1681): 28%

* Per AKIN definition: increase in creatinine by

0.3mg/dL / 26.5mmol/L

INCIDENCE OF CRS

Forman DE et al. J. Am. Coll. Cardiol. 2004;43:61-67

Krumholz HM et al. Am. J. Cardiol. 2000; 85:1110-1113

www.nhlbi.nih.gov/research/reports/2004-cardiorenal

CRS category Pathophysiology

I Acute HF → AKI

II Chronic HF → CKD

III AKI → Acute HF

IV CKD → Chronic HF

V Systemic disease → RD + CFRonco C et al. Intensive Care Med. 2008;34:957-962

THE LOW-FLOW STATE HYPOTHESIS

In cardiac failure:

1. Increased SNS

2. Decreased FeNa

3. Myocardial fibrosis

HAEMODYNAMICS AND RENAL FUNCTION

Evaluation Study of Congestive Heart Failure and Pulmonary Artery

Catheterization Effectiveness (ESCAPE):

• In 194 patients randomized to pulmonary artery catheter-guided

treatment of cardiac failure:

Renal parameter Cardiac parameter Correlation*

Baseline creatinine

Baseline eGFR**

Baseline PCWP

Baseline cardiac index

Baseline SVR

None

Worsening renal function

Baseline PCWP

Baseline cardiac index

Baseline SVR

None

Worsening renal function

Change in PCWP

Change in cardiac index

Change in SVR

None

Baseline creatinine

Baseline eGFR** RAPr = +0.165, p = 0.03

r = -0.195, p = 0.01

Nohria A et al. JACC 2008;51:1268-1274

*Pearson’s correlation

**MDRD

HAEMODYNAMICS AND RENAL FUNCTION /2

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

Damman K et al. J. Am. Coll. Cardiol. 2009;53:582-589

OLD TRICKS IN OLD DOGS

Winton FR. J. Physiol. 1931;72:49-61

Blake WD et al. Am. J. Physiol. 1949;157:1-13

Increasing venous pressure

Inc

rea

sin

g u

rete

ric

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w (

L=

test,

R=

co

ntr

ol)

INTRABDOMINAL PRESSURE IN CCF• n = 40, admitted with acute CCF

• Mean LVEF 19%

• 24/40 (60%) had IAP ≥ 8mmHg

(normal = 5 – 7 mmHg)

• All 24 were asymptomatic of IAP

• Change in IAP correlated with change

in creatinine

Mullens W et al. J. Am. Coll. Cardiol. 2008;51:300-306

Doty JM et al. J. Trauma 2000;48:874-877

Doty et al. J. Trauma 1999;47:1000-1003

Re

na

l p

are

nc

hy

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ow

Re

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l v

ein

pre

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re

NEUROHORMONAL CROSS-TALK

• Haemodynamic perturbation in

cardiac failure triggers

neurohormonal adaptation which

preserves cerebral and cardiac

perfusion at the cost of renal

perfusion

• Implicated systems / messengers

include:

• SNS

• Renin-aldosterone-angiotensin

• Vasopressin

• Endothelin-1

Kazory A. Am. J. Coll. Cardiol. 2010;106:694-700

RAS AND RENAL INFLAMMATION

Homma T et al. Am. J. Physiol. 2012;302:F750-761Terada Y et al. Kidney Int. 1993;43:1251-1259

CRS 2 /4

AT1R

RAS AND RENAL INFLAMMATION /2

Li N et al. Clin. Chem. Acta 2010;411:1963-1968

Sham, CD4 AII, CD4

Crowley SD et al. Am. J. Physiol. Renal Physiol. 2008;295:F515-524

Madhur MS et al. Hypertens. 2010;55:500-507

Ruiz-Ortega et al. J. Immunol. 1998;161:430-439

IL-17

FEEDING THE FIRE: OXIDATIVE STRESS

Sachse A. J. Am. Soc. Nephrol. 2007;18:2439-2446

Lopez B et al. Hypertension 2003;42:1150-1156

Tojo A et al. Hypertension 2002;40:834-839

Heymes C et al. J. Am. Coll. Cardiol. 2003;41:2164-71

Control,

NADPH

CCF,

NADPH

CCF,

NADPH

Control,

NADPH

UNIFIED THEORY OF EVERYTHING

Bongartz LG et al. Hypertension 2004;43:14

CRS 1

CRS 2

CRS 3

CRS 4

THERAPY RATIONALES

1. Treat overload:

1. Reduce intra-abdominal and renal venous pressures to improve renal

perfusion

2. Reduce RV dilatation to improve LV filling and forward ejection

3. Improve LV stroke volume and decrease SVR

2. Improve cardiac function:

1. Improve renal perfusion to facilitate diuresis and clearance

3. Block activation of pro-inflammatory / pro-fibrotic

adaptive responses

REDUCE OVERLOAD

Wilson JR et al. Am. J. Med. 1981;70:234-239 Brilla CG et al. Circ. Res. 1990;67:1355-1364

“Diuretic agents have long been considered to be

initial and essential part of the management of the

CRS patients. However, limited clinical data

suggest their beneficial role”

Koniari K et al. Int. J. Nephrol. 2011;2011:194910

Long term diuresis

OPTIMIZING FLUID LOSS

“Many factors may be responsible for diuretic resistance [in CRS], such as delayed

intestinal absorption of oral drugs due to mucosal edema, decreased renal perfusion,

decreased diuretic excretion into the urine, …”

Koniari K et al. Int. J. Nephrol. 2011;2011:194910

Parameter Infusion vs. bolus

Urine output WMD +271cc

(93.1 – 449)

p < 0.01

Creatinine (mg/dL) WMD -0.54

(-0.57 - -0.51)

p < 0.01

Clinically relevant

electrolyte

disturbance

RR 1.47

(0.52 – 4.15)

p = 0.5

All cause mortality RR 0.52

(0.38 – 0.71),

p < 0.01

Salvador DRK et al. Coch. Data. Syst. Rev. 2005;2:CD003178 Costanzo MR et al. J. Am. Cardiol. Coll. 2007;49:675-683

ULTRAFILTRATION AND HAEMODYNAMICS• Ultrafiltration by CVVHD Qb 100ml/min UF targeting 10% increase in Hct, n = 24

“A 1:1 reduction in LV and RV constraint might be due to removal of increased lung, pleural, and ascitic fluid…

…removal of the constraining effect of overhydration reduces ventricular filling pressure and improves

diastolic properties, improving cardiac performance”Marenzi GC et al. J. Am. Coll. Cardiol. 2001;38:963-968

VASODILATORSVasodilators do not appear to be effective in CRS and may be harmful:

Costanzo MR et al. Am. Heart J. 2007;154:267=277

Chen HH et al. JAMA 2013;310:2533-2543

INOTROPESDiuretic

Diuretic

Diuretic + DA

Diuretic + DA

Varriale P et al. Clin. Cardiol. 1997;20:627-630 Giamouzis G et al. J Cardiac Fail. 2010;16:922-930

“RENAL DOSE” DOBUTREX

Inotrope Receptor

Dopamine • DA2 (< 2 micg/kg/hr)

• b1 (5 – 10micg/kg/hr)

• a (> 10 micg/kg/hr)

Dobutamine

(Dobutrex)

• b1 (+isomer, potent)

• B2 (+ isomer, weak)

• a2 (-isomer)

DRD1

ADRB2

ADRA1D

Elkayam U et al. Circulation 2008;117:200-205

ADRB1

DOBUTREX IN CRS

Al-Hesayen A, Parker JD. J Cardiovasc Pharmacol. 2008;51:434-436

Ichai C et al. Crit Care Med 2000; 28:921-928

RAS BLOCKADE

Inder S et al. Circulation 2009;120:1577-1584Lesogor A et al. Eur. J. Heart Fail. 2013;15:1236-1244

WORSENING RENAL FUNCTION WITH RAS I

Mean decrease in

eGFR

p

Vasartan cohort 6.7 ml/min/1.73m2

< 0.001Placebo cohort 2.9 ml/min/1.73m2

Lesogor A et al. Eur. J. Heart Fail. 2013;15:1236-1244

Kiernan MS et al. Eur. J. Heart Fail. 2012:14:1401-1409

WORSENING RENAL FUNCTION WITH RASI

Kiernan MS et al. Eur. J. Heart Fail. 2012:14:1401-1409

Testani JM et al. Circ. Heart Fail. 2011;4:685-691

Predictor Worsened renal

function

Losartan dose (150 : 50mg) 1.47 (1.27-1.70),

p < 0.0001

Age 1.11 (1.03-1.20),

p = 0.004

Aldosterone antagonist 1.28 (1.10-1.49),

p = 0.001

Diuretic use 1.36 (1.10-1.67),

p = 0.004

Diabetes 1.47 (1.27-1.70),

p < 0.0001

LVEF (per % higher) 0.98 (0.97-0.99),

p = 0.0002

Hb 1.06 (1.01-1.11),

p = 0.02

Baseline creatinine 2.35 (2.13-2.59),

p < 0.0001

Gender, b-blocker,

antiarrhythmic

N/S

OPTIMIZATION OF HAEMOGLOBIN

• n = 142, mean Hb 11.9 ± 1.5g%

• Intervention study using ESA with n = 26:

Parameter Before

intervention

After

intervention

p

Hct (vol%) 30.14 ± 3.12 35.9 ± 4.22 < 0.05

Hb (g/dL) 10.16 ± 0.95 12.10 ± 1.21 < 0.05

Ferritin (micg/L) 177.07 ± 113.80 346.73 ± 207.40 < 0.05

Creatinine (mg%) 2.59 ± 0.77 2.73 ± 1.55 N/S

LVEF (%) 27.7 ± 4.8 35.4 ± 7.6 < 0.05

Number of hospitlizations 2.72 ± 1.21 0.22 ± 0.65 < 0.05

NYHA (0 – 4) 3.66 ± 0.47 2.66 ± 0.70 < 0.05

Silverberg DS et al. J. Am. Coll. Cardiol. 2000;35:1737-1744

LEFT VENTRICLE ASSIST DEVICES

Tromp TR et al. Heart Fail. Rev. 2015;20:519-532

Hasin T et al. J. Am. Coll. Cardiol. 2012;59:26-36

Ootaki C et al. J. Thoracic Cardiovasc. Surg. 2008;136:150-158

H & E AT1R

KIDNEY ASSIST STRATEGIES

Kazroy A. World J. Cardiol. 2015;7:392-396

Zolty R et al. Am. J. Transplant. 2008;8:2219-2224

n = 67 Pre HD On HD p

Hospital

admission

rate (/yr)

0.79

± 1.32

0.22

± 0.650.0001

Duration

of annual

hospital

stay

(days)

11.4

± 21.4

3.7

± 10.40.011

Survival 1-year: 81%

2-year: 61%

3-year: 52%

4-year: 47%

5-year: 39%

Leskovar B et al. Clin. Nephrol. 2017;88:57-60

Study EF GFR Comment

Koch 43.5 19.2 Improved NYHA class

Nunez 40 33

Improved NYHA class,

reduced hospitalization for

CCF

Bertoli 30 21

Improved NHYA class,

reduced hospitalization,

improved EF

Courivaud 38 33.5Reduced hospitalization,

improved cardiac function

SUMMARY

• Cardio-renal syndrome is not uncommon - ~ 1/3 of HF admissions will develop AKI

• The presence of CRS predicts a poorer long-term outcome

• The development of CRS results in activation of systems leading to chronic cardiac and renal injury

• In the context of anticipated poor outcome therapy is largely palliative:

• Diuresis relieves renal venous pressure and may improve renal function

• Long-term diuretic use when overload is corrected / improved will lead to further renal

injury

• Inotropes are only indicated in the context of cardiogenic shock

• “Renal dose dobutrex” has no scientific basis

• Vasodilators may be harmful

• RAS blockade is a rational therapy – accept MINOR GFR deterioration for long-term benefit

• Once CRS is established, cardiac / renal replacement therapies do not substantially alter

outcomes (? dual cardiac / renal transplant would be required)