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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 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
GP Female GP Black GP White General Population Dialysis Male Dialysis Female Dialysis Black
1 .1
.01
Dialysis White
73.9
60
Prevalence (%)
40
35.5 14.8
20
LVH
LVD
Risk of CV Death Related to Systolic Function and LVH in 254 ESRD Patients
*P= 0.001
* *
**PP=0.02
Survival
Normal
Months
Parfrey et al. Nephrol Dial Transplant. 1996;11:1277-1285.
2007 ADR
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
Months
KI 67:333, 2005
P=0.02
Months
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.
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
1 2 3 4 5
Stage of CKD 2 3 4
Keith et al, Arch Intern Med 164:659, 2004 Death more common than kidney failure at all stages
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
CAD
MI
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.
N = 6526
30 20 10 0 > 70 50 - 70 < 50 GFR (mL/min/1.73 m2) 18.6 25.3
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
Between a Rock and a Hard Place: Treating CHF in Patients with CKD
11
5 4
Mortality RR
3 2 1 0
<21% 21-25% 26-30% >30%
Circ 2000;102:203
GFR (ml/min)
Ejection Fraction
GFR (ml/min)
>90 60-89 30-59 15-29 <15
CV Risk (OR)
? (?proteinuria) 1.5 2-4 4-10 20-1000
12
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
13
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%
Loop Diuretics
Marked Activation of the RAAS
Plasma Renin Activity (ng/mL/h) 50
10
2.5
0.5
Before Diuretic (n = 12) After Diuretic (n = 11)
Effects of Angiotensin II
Angiotensin
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
High Low
0.6
Low
0.2
12
18
24
30
36
P=0.001
5 4 3 2 1
Ultrafiltration
0
Diuretic
15
100 80 60 40 P= 0.037 20 0 0 10 20 30 40
50 Days
60
70
80
90
R2=0.73 P<0.001
AVP log10
II
III
IV
16
Inpatient
Months in Study
JAMA 2007;297:1319
17
Circ 1997;95:1363
BG9719
15
GFR (%change
5 -5
Placebo
BG9719 + Furosemide
Furosemide
2000
2500
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
18