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The Cardio-Renal Syndrome

Alan S. Kliger MD Hospital St. Raphael & Yale University New Haven CT

Cardiorenal Syndrome?
Pathophysiologic condition in which combined cardiac and renal dysfunction amplifies progression of failure of the individual organ to lead to astounding morbidity and mortality ( Eur Heart J 2005;26:11) Presence or development of renal dysfunction in patients with heart failure (Heart Failure Rev 2004;9:195) A syndrome in which the heart or kidney fails to compensate for impairment of the other organ, resulting in a vicious cycle that will result in decompensation (Curr Heart Fail Rep 2004;1:113)

Burden of Heart Failure in US


Affects 4.8 million Americans, 1% (age 50-59), 10% (age 80-89) 550,000 diagnoses each year (75% w/ HTN) Expected prevalence of 6 million in year 2010 ~1,000,000 Hospital Discharges (6.5 million days) 80% of men and 70% of women under age 65 with CHF will die within 8 years <15% of women survive a decade. 1-year mortality 15%. Death from CHF rose 145% in past 20 yrs (> 280,000) with a sudden cardiac death rate 6-9 times the general population

Burden of CKD in US
20 million Americans with CKD (1 of 9 adults) 470,000 treated for kidney failure 336,000 on dialysis and 136,000 s/p transplant 70,000 deaths yearly related to kidney failure 73,019 patients awaiting transplant and 18 patients die each day on the list Leading causes are diabetes (36% of all cases) and poorly controlled hypertension (23%) HD/PD patients have a 40% incidence of CAD, 40% CHF, and 70% LVH with CVD mortality 10-20 times the general population
National Kidney Foundation 2007

Cardiovascular Disease Mortality


100
GP Male

10 Annual Mortality (%)


Dialysis Population

GP Female GP Black GP White General Population Dialysis Male Dialysis Female Dialysis Black

1 .1

.01

Dialysis White

25-34 35-44 45-54 55-64 65-74 75-84 >85 Age (yr)


Adapted from Meyer KB, Levey AS. J Am Soc Nephrol. 1998;9(suppl):S31-S42.

Patients With Kidney Disease Have a Higher Incidence of Heart Disease

LVH Is Present in 74% of ESRD Patients at Initiation of Dialysis


80

73.9

60

Prevalence (%)

40

35.5 14.8

20

LVH

LVD

Systolic dysfunction N = 433

Note: Patients could have more than one disorder.


LVD = left ventricular dilatation; LVH = left ventricular hypertrophy. hypertrophy. Foley et al. Kidney Int. 1995;47:1861995;47:186-192.

Risk of CV Death Related to Systolic Function and LVH in 254 ESRD Patients
*P= 0.001

* *
**PP=0.02

JASN 15:1029, 2000

CVD After Kidney Failure Is a Risk Factor for Death


1.0 0.9 0.8

Survival

Normal

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 6 12 18 24 30 36 42 48 54 60 66 72

Concentric LVH LV Dilatation Systolic Dysfunction

Months
Parfrey et al. Nephrol Dial Transplant. 1996;11:1277-1285.

432 ESRD pts surviving dialysis 6 mo followed with echocardiogram

Cardiovascular mortality rates in prevalent ESRD patients


Figure hp.5

Period prevalent ESRD patients; unadjusted.

2007 ADR

Pathological Characteristics of Cardiomyopathy in Dialysis Patients


40 dialysis patients and 50 control patients with dilated cardiomyopathy had endomyocardial biopsies Both groups had a decrease in EF (34/35%) Classification by NYHA (%) Control HD I 8 0 II 40 28 III 36 48 IV 16 25
KI 67:333, 2005

A 63 yo Man on HD for 7.3 years Bizarrely Shaped Myocytes with Irregular Enlarged Nuclei

KI 67:333, 2005

56 yo Man on HD for 7.1 years Widespread Fibrosis Present; Patient Died of Ventricular Arrhythmia 1.1 Year after Biopsy

KI 67:333, 2005

56 yo Man on HD for 6.8 Years. Small Amount of Fibrosis Present and No Cardiac Event 3.8 Years After Biopsy

KI 67:333, 2005

Cumulative Survival for Cardiac Death Stratified by Extent of Fibrosis

Cumulative event free survival rate, %

Months

KI 67:333, 2005

Importance of CAC Score in Incident ESRD Patients


Survival distribution function

P=0.02

CAC=0 CAC1-400 CAC >400

Months

Kidney International 2007; 438-441

Ischemic Heart Disease Risk is Related to Microalbuminuria and Blood Pressure

6 5

Normoalb Microalbu

1 2 .

2.2 4.9

4.8 1 0 . 5

Relative 4 3 risk
2 1 0 SBP <140 SBP 140-160 SBP>160 Microalbuminuria Normoalbuminuria

N = 2,085, 10 year follow up. Borch-Johnsen et al. Arterioscler Thromb Vasc Biol. 1999;19:1992.

Albuminuria and CV Events in HOPE


DM: 3498 - 32.6% Non DM: 5545 - 14.8%
All Diabetes No Diabetes

Cardiovascular Events (%)

30 25 20 15 10 5 0
1-2 3 4 5 6 7 8 9 10

Albumin/Creatinine Ratio

ACR 2mg/mmol
JAMA 2001;286(4):421

The Stages of CKD


Stage Description Kidney Damage with Nl or GFR Mild GFR Moderate GFR Severe GFR Kidney Failure GFR Prevalence Prevalence (mL/min/1.73 (000s) (%) m2) >90 6060-89 3030-59 1515-29 <15 or Dialysis 5,900 5,300 7,600 400 300 3.3% 3.0% 4.3% 0.2 0.1

1 2 3 4 5

CKD Stage and Outcomes:


Adjusted Hazard Ratios
Est GFR > 60 4545-59 3030-44 1515-29 < 15 Death Any Cause 1.00 1.2 1.8 3.2 5.9 Any CV Event 1.00 1.4 2.0 2.8 3.4 Any Hosp. 1.00 1.1 1.5 2.1 3.1

Go et al, NEJM 351:1296, 2004

Outcomes in Chronic Kidney Disease


Rates per 100pt-yrs
CHF ASVD Death CKD CKD + DM 30.7 52.3 35.7 49.1 17.7 19.9 RRT 1.6 3.4

Foley et al JASN 16:489, 2005

Outcomes for CKD patients


Rate (%) of Renal Replacement Therapy and Death at 5 years

Stage of CKD 2 3 4

RRT 1.1 1.3 19.9

Death 19.5 24.3 45.7

Keith et al, Arch Intern Med 164:659, 2004 Death more common than kidney failure at all stages

Traditional CV Risk Factors


Hypertension Diabetes Dyslipidemia Older age Smoking

All are highly prevalent in CKD patients


Muntner et al, JASN 16:529, 2005

Non-Traditional Risk Factors for CHD in CKD Patients


Metabolic Syndrome Increased Arterial Stiffness Anemia Ca/Phos/Bone Metabolism Abnormalities Proteinuria Chronic Inflammatory State Uremic Toxins

Traditional Risk Factors

Non-modifiable

Age Make Gender Family History Diabetes Hypertension Dyslipidemia Smoking Hyperhomocystinemia Oxidative stress Inflammation Low serum albumin Anemia High PTH High PO4 Low GFR Increased ET High CRP Albuminuria, High ADMA

CHF LVH

+
Modifiable

Arterial Stiffness
PVD

Uremia-related Risk Factors

CAD

MI

Qunibi, Henrich, Berl

Conclusions (part 1)
CKD is common CKD increases all-cause mortality CKD increases CV mortality CKD increases CHF Albuminuria increases CV events CKD patients are much more likely to die than to progress to ESRD & dialysis Lesson: Treat CVD and its risk factors in CKD patients: biggest bang for the buck.

Chronic Kidney Disease alone is an independent risk factor for CVD

Even Mild CKD Is a Risk Factor for Death


Studies of Left Ventricular Dysfunction
40 All-cause mortality (%)* 37.4

N = 6526
30 20 10 0 > 70 50 - 70 < 50 GFR (mL/min/1.73 m2) 18.6 25.3

Cox proportional hazards model


GFR is independent predictor of mortality Risk ratio = 1.04 per 10 mL/min/1.73 m2 (P < 0.032)

*Unadjusted, 33.433.4-month followfollow-up AlAl-Ahmed et al. J Am Soc Nephrol. Nephrol. 1999;10:152A.

Weiner, JASN 15:1312, 2004

Time to Renal Replacement Therapy by CVD


Probability of remaining event free 1.0 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48

No CVD
Log-Rank Test P = 0.0041 .

Any CVD

Months

10

Association between Renal Function and Mortality in 118,753 pts > 65yo who suffered an AMI

Smith, G. L. et al. J Am Soc Nephrol 2008;19:141-150

Adjusted survival curves for CCr, with follow-up to 10 yr

Survival of 6,640 Patients with LVSD According to Rate of eGFR Decline

Khan, N. A. et al. J Am Soc Nephrol 2006;17:244-253

Between a Rock and a Hard Place: Treating CHF in Patients with CKD

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GFR and Survival in PRIME II:


Cox-adjusted Survival analysis
1.0 0.9 Proportion Survival 0.8 0.7 0.6 0.5 0.4 0.3 0 250 500 Days 750 1000 1250
Circ 2000;102:203
<44 ml/min >76 ml/min 59-76 ml/min 44-58 ml/min

1906 pts NYHA III/IV

GFR, EF and Survival in PRIME II

5 4
Mortality RR

3 2 1 0
<21% 21-25% 26-30% >30%
Circ 2000;102:203

<44 44-58 59-76 >76

GFR (ml/min)

Ejection Fraction

Chronic Kidney Disease and CV Risk


Stage
1 2 3 4 5

GFR (ml/min)
>90 60-89 30-59 15-29 <15

CV Risk (OR)
? (?proteinuria) 1.5 2-4 4-10 20-1000

Microalbuminuria increases risk 2 4 fold


Schiffrin et al. Circ 2007;116:85

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CHF: Worsened Renal Function in Hospital


27% of 1,004 pts had worsened renal function (>0.3mg/dl)
Hazard Ratio

History of CHF (1) Diabetes (1) SBP> 160 (1) 1.5<creat<2.5 (2) Creat = 2.5 (3)

1.3 (1.01-1.7) 1.4 (1.1-1.8) 1.4 (1.1-1.7) 2.1 (1.6-2.8) 3.5 (2.5-4.8)
Score = 0 10% risk Score = 4 53% risk

52% of WRF develops by day 3 and results in:


7X increase in risk of death 3X increase in length of stay 2X increase in complications No relation to hypotension or hypovolemia
Krumholz. JACC 2004;43:61

Pathophysiologic Link Between Heart Failure and Renal Insufficiency


Intrinsic renal disease
Renal vascular disease (pre-renal, intrarenal) Nephron loss (age, renal disease)

Inadequate renal perfusion


RAAS activation Hypovolemia Inadequate cardiac output ( vasoconstriction/pump failure) Hypotension Abnormally high central venous pressure Drug induced NSAIDs, cyclosporine, tacrolimus, ACEI, ARB

Fonarow. Am J Med 2006; 119(12)

Chronic Cardiac Failure


Increased Cardiac Filling Pressures Decreased Baroreceptor Sensitivity

Sodium and water Retention

Sympathetic and RAAS Activity

Resistance to Natriuretic Peptides

Failure to Escape from Aldosterone

Proximal Tubule Sodium and Water Reabsorption

Decreased Distal Na and Water Delivery

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Weight Loss During Hospitalization for Heart Failure


35 30

33% 24%

Patients (%)

49%
11%

25 20 15 10 5 0
(<-20) (-20 to -15)(-15 to -10)(-10 to -5) (-5 to 0) (0 to 5) (5 to 10) (>10)

13% 7% 6%

3%

2%

Change in Weight (lbs)


Fonarow GC. Rev Cardiovasc Med. 2003; 4 (Suppl. 7): 21

Loop Diuretics
Marked Activation of the RAAS
Plasma Renin Activity (ng/mL/h) 50

10

Mean Confidence Interval

2.5

0.5
Before Diuretic (n = 12) After Diuretic (n = 11)

Bayliss J et al. Br Heart J. 1987;57:1722.

Effects of Angiotensin II
Angiotensin

Adrenal Cortex Aldosterone

Kidney

CNS

Periph NS

Vascular SM

Symp NS Vasoconstriction

Na, H2O Thirst Distal Na Vasopressin Reabsorption Reabsorption Na Appetite Maintain or Increase ECFV Total Peripheral Resistance

14

Diuretic Resistance in CHF:


Predictor of Mortality PRAISE 1,153 pts
Hazard Ratios CT ratio >57% BUN> 22 mg/dl Sys BP <118 HR > 80 bpm Ischemic High Diuretic Dose* Metolazone use Age> 65 Total Mort 1.75 1.65 1.64 1.51 1.49 1.37 1.37 1.33 Sudden Death 1.75 1.70 -1.45 -1.39 --Pump Fail 2.16 2.06 1.97 1.97 2.09 1.51 -1.67

*High Dose = 175 3.3 mg Am Heart J 2002;144:31

PRAISE: Diuretics and Vasodilators


1.0 Diuretic High 0.8 Total Mortality Chi-square = 33.83 P = 0.0001 0.4
240 160 526 224

ACEI Low High Low High

High Low

0.6

Low

0.2

12

18

24

30

36

Months from Randomization


AHJ 2002;144(1):31

Ultrafiltration in Decompensated CHF: UNLOAD


200 patients w/ CHF and volume overload 10% 90 day mortality Ultrafiltration at 241 ml/hr for 12.3 12 hrs Mean furosemide dose of 181 121 mg 68 continuous/32 bolus
Creat> 0.3: 22.6% Ultrafiltration - 19.8% Diuretic (p=0.7)
6

Weight Loss (kg)

P=0.001
5 4 3 2 1

Ultrafiltration
0

Diuretic

Costanzo, M. R. et al. J Am Coll Cardiol 2007;49:675-683

15

Ultrafiltration in Acutely Decompensated CHF: UNLOAD


% Free from Re-Hospitalization

100 80 60 40 P= 0.037 20 0 0 10 20 30 40

Ultrafiltration (16 events)

Standard care (28 events)

50 Days

60

70

80

90

Costanzo, M. R. et al. J Am Coll Cardiol 2007;49:675-683

Peripheral Veno-Venous Ultrafiltration

CHF Solutions, Inc.

Arginine Vasopressin Levels in CHF


2 1.8 1.6 1.4

R2=0.73 P<0.001

AVP log10

1.2 1 0.8 0.6 0.4 0.2 0

II

III

IV

NYHA Functional Class


Price et al. Circ 2004;109:2550

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V2 Blockade in Hospitalized Patients with CHF


Tolvaptan: an orally active V2 receptor blocker Body Weight
N= 4133 Change from Baseline, Kg

Inpatient

After Discharge, wks


JAMA 2007;297:1319

V2 Blockade in Hospitalized Patients with CHF


Tolvaptan: an orally active V2 receptor blocker
Cardiovascular Mortality or Heart Failure Hospitalization
Proportion Without Event

Months in Study
JAMA 2007;297:1319

Adenosine Antagonism in Heart FAilure


Adenosine: released in response to myocardial ischemia Afferent arteriolar vasoconstriction with resultant reduced renal blood flow and GFR Increased proximal and distal tubule Na reabsorption Acute increase in Na delivery to the distal tubule causes an increase in adenosine concentrations resulting in decreased GFR via tubuloglomerular feedback at the macula densa and afferent arteriole A1 receptor antagonism maintains renal function by vasodilation of the afferent arteriole and interruption of the tubuloglomerular feedback loop while causing natriuresis

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Plasma Adenosine Levels in Chronic Heart Failure

Circ 1997;95:1363

A1 Adenosine Antagonism in CHF

BG9719

15

GFR (%change

5 -5
Placebo

BG9719 + Furosemide

-15 -20 0 500 1000 1500

Furosemide

2000

2500

Urine Output (ml)


0-8 hrs, Day 1 - Baseline

Circ 2002;105:1348

Conclusions (part 2)
CKD is an independent risk factor for CVD Inpatient treatment of CHF often results in worse renal function Diuretic resistance predicts poor survival Promising areas for more study:
Ultrafiltration devices Vasopressin 2 blockade Adenosine antagonists

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