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UK Nephrology, Bone and
Mineral Metabolism
The “New” Cardiorenal Syndrome
Peter Sawaya, MD, FACP, FASN
Professor of Medicine
Fellowship Program Director
University of Kentucky
The “Old” Cardiorenal Syndrome
Heart
Kidney
PerfusionNa
Retention
UK Nephrology, Bone and
Mineral Metabolism
What is the estimated rate of cardiovascular
disease in patients with CKD stage 4? (eGFR 15-29 ml/min/1.73 m2; per 100 person-year)
A) 5-10
B) 11-20
C) 21-30
D) 31-40
E) > 40
UK Nephrology, Bone and
Mineral Metabolism
CKD & CVD
2.13.6
11.3
21.8
36.6
0
10
20
30
40
>60 45-59 30-44 15-29 <15Rate
of
Card
iovasc
ula
r E
ven
ts
(per
100 p
erso
n-y
r)
eGFR (ml/min/1.73m2)
Go et al., NEJM 2004
UK Nephrology, Bone and
Mineral Metabolism
Hazard Ratio for Death after MI
According to the eGFR
11.14
1.34
1.7
0.0
0.4
0.8
1.2
1.6
2.0
>75 60-75 45-60 <45
Anavekar et al. NEJM 2004
eGFR (ml/min/1.73m2)
Ad
just
ed H
R f
or
Dea
th
**
*
UK Nephrology, Bone and
Mineral Metabolism
CKD & CVD
Traditional risk factors
The metabolic syndrome
LVH and myocardial remodeling
Anemia
Increased inflammatory/oxidative stress
The “micro” uremic melieu
Endothelial dysfunction
Proteinuria
Abnormal mineral metabolism
Low physical activity
“Renalism”
UK Nephrology, Bone and
Mineral Metabolism
CKD and CVD Risk FactorsNHANES III, N = 15,800
0%
20%
40%
60%
80%
100%
120%
Normal 60-89 30-59 <30
eGFR (ml/min/1.73m2)
Foley et al., Mayo Clinic Proc 2005
% >
2 R
isk
Fact
ors
Smoking, Obesity, HTN, Hypercholesterolemia,
CRP, HgbA1C, Homocysteine, Anemia, UP/C
UK Nephrology, Bone and
Mineral Metabolism
CKD and the Metabolic SyndromeNHANES III: 6217 Patients
0
2
4
6
8
10
0 1 2 3 4 5Metabolic Syndrome Components
Chen et al., Ann Intern Med 2004
CK
D P
reva
len
ce %
Hypertriglyceridemia (>150), Low HDL (<40;50),
Central Obesity (>40"), Increased FBS (>110) and
HTN (>130/85) – ATP III Guidelines
UK Nephrology, Bone and
Mineral Metabolism
CKD and the Metabolic SyndromeNHANES III
0
1
2
3
4
5
6
0 or 1 2 3 4 5
Metabolic Syndrome Components
Chen et al., Ann Intern Med 2004
OR
for
CK
D
UK Nephrology, Bone and
Mineral Metabolism
CKD vs. Hypercholesterolemia
0
1
2
3
4
5
C 150 -
G > 60
C 200 -
G 45-59
C 250 -
G 30-44
C 300 -
G 15-29
G < 15
Cholesterol
eGFR
MRFIT, JAMA 1984
Go et al., NEJM 2004
UK Nephrology, Bone and
Mineral Metabolism
HTN, CKD & CVD
281 patients with essential HTN and normal
GFR, Madrid, Spain
Followed for an average 13 years
15% developed CKD (eGFR < 60)
41% of pts with CKD had CVD
Only 13% of pts without CKD had CVD
CKD HR for CVD = 2.5 (multivariate analysis)
Segura et al., JASN 2004
UK Nephrology, Bone and
Mineral Metabolism
What is the most common cardiac
abnormality in ESRD patients?
A) Mitral regurgitation
B) Tricuspid regurgitation
C) Systolic dysfunction
D) Diastolic dysfunction
E) Both, systolic and diastolic dysfunction
UK Nephrology, Bone and
Mineral Metabolism
LVH & LV Dysfunction in
Incident HD Patients
LVH 62%
Diastolic dysfunction 57%
Diastolic and systolic dysfunction 24%
Systolic dysfunction 5%
Normal 10%
Vankatesan & Henrich, JASN 1998
UK Nephrology, Bone and
Mineral Metabolism
LV Fibrosis in ESRD Patients with
Dilated Cardiomyopathy
0
10
20
30
40
50
Myocyte Diameter Fibrosis
Control
Dialysis
Aoki et al., KI 2005
%
> 40 mm > 45 %
UK Nephrology, Bone and
Mineral Metabolism
LV Fibrosis
A picture is worth a thousand words!
Normal Fibrosis
UK Nephrology, Bone and
Mineral Metabolism
LV Fibrosis in ESRD Patients and
Risk of Death
Aoki et al., KI 2005
Multivariate Analysis
Fibrosis >30% = HR 27.1*
UK Nephrology, Bone and
Mineral Metabolism
What is the most common cause of
cardiovascular death in ESRD patients?
A) Acute myocardial infarction
B) Pulmonary edema
C) Chronic CHF
D) Sudden death
E) Atrial fibrillation with RVR
UK Nephrology, Bone and
Mineral Metabolism
Sudden Cardiac Death
0
20
40
60
80
Hemodialysis Peritoneal Dialysis
% of Cardiac Deaths % of All-Cause Mortality
USRDS 2006
UK Nephrology, Bone and
Mineral Metabolism
Adapted from GM London,
Seminars in Dialysis, 2003
Cardiac Remodeling
Hypertrophy Fibrosis
Pressure/Volume
Overload
Sympathetic
/ RAAS
Local
Factors Inflammation
UK Nephrology, Bone and
Mineral Metabolism
Anemia and LVH in CKD
Reduced oxygen delivery to the myocardium
Increased cardiac output and reduced SVR
Increased oxidative stress
Activation of sympathetic system
JS Berns, UpToDate® 2008
UK Nephrology, Bone and
Mineral Metabolism
Anemia in CKD: NHANES III(Hgb < 12 M; < 11 F)
1.81.3
5.2
44
1
10
100
>90 60-89 30-59 15-29
Pre
vale
nce
of
An
emia
(%
)
eGFR (ml/min/1.73m2)
Astor et al., Arch Intern Med 2002
Inflammation/Oxidative Stress & CKD
Healthy subjects CKD patients P value
CRP mg/L 1.8 3.9 0.02
IL-6 pg/mL 2.1 6.4 0.001
Thiols mol/L 415 303 <0.001
Carbonyls
nmol/mg
protein
0.029 0.061 <0.001
F2-isoprostanes
ng/mL0.036 0.046 <0.001
Oberg et al., KI 2004
UK Nephrology, Bone and
Mineral Metabolism
Inflammation & CKD
Decreased clearance of proinflammatory
cytokines: TNFα , IL1, IL6
Altered intestinal permeability: Endotoxemia
Increased oxidative stress: Free radical
production & AGE accumulation
Decreased levels of antioxidants: Low vitamin C
Comorbid conditions: Periodontal disease
Kalantar-Zadeh & Kopple, UpToDate® 2008
UK Nephrology, Bone and
Mineral Metabolism
“The Micro Uremic Milieu”
UK Nephrology, Bone and
Mineral Metabolism
New Uremic Toxins
Middle Molecules Dinucleoside
polyphosphate
Ang II variants
α-fibrinogen fragments
AGEs
Oxidation products
Cytokines
Protein-Bound Dinucleoside
polyphosphate
Cytokines
Phenols
Indoles
AGEs
Phenylacetic acid
Others Guanidines, ADMA,
SDMA
Adapted from R. Vanholder,
Advances in CKD 2008
UK Nephrology, Bone and
Mineral Metabolism
Dinucleoside Polyphosphates
Two nucleosides linked by a variable
number of phosphates
Increased concentration in ESRD
patients
Induce smooth muscle cell
proliferation
Jankowski et al., KI 2001
UK Nephrology, Bone and
Mineral Metabolism
Vascular Smooth Muscle Cells
Proliferation
0
100
200
300
400
500
600
700
Control Patients C-PPADS P-PPADS
Arb
itra
ry U
nit
s
Adapted from Jankowski et al., KI 2001
UK Nephrology, Bone and
Mineral Metabolism
Uridine Adenosine Tetraphosphate
(Up4A)
Endothelium-derived
Potent vasoconstrictor
Nonpeptidic
Accumulates in renal failure
Jankowski et al.,
Nature Medicine 2005
UK Nephrology, Bone and
Mineral Metabolism
P-Cresylsulphate
From the metabolism of tyrosine and
phenylalanine by intestinal flora
MW 108 Da, but highly protein-bound
Accumulates in renal failure
Significantly increases the percentage of
leukocytes displaying oxidative burst
activity
Schepers et al., NDT 2007
UK Nephrology, Bone and
Mineral Metabolism
Asymmetric Dimethyl Arginine
(ADMA)
Kielstein and Zoccali, AJKD 2005
Nucleulus
Proteins
Methylated Protein
Shear stress Oxidized lipoprotein
ADMAVasoconstriction
?AT1Nitric oxide
UrineDDAH
DDAH: Hyperlipidemia, hyperglycemia, smoking, hyperhomocysteinemia
UK Nephrology, Bone and
Mineral Metabolism
ADMA & CV Events
Adapted from:
Kielstein et al., AJKD 2005
Zoccali et al., Lancet 2001
Plasma ADMA
Ha
zard
Ra
tio
UK Nephrology, Bone and
Mineral Metabolism
All-Cause Mortality and Proteinuria
Taiwan Health Management Institution Study (462,293 Adults screened – 56,977 CKD)
0
1
2
3
4
5
6
eGFR >90 60-89 45-59 30-44
Normal Proteinuria Minimal Proteinuria Overt Proteinuria
Lancet 2008, 371:2173-82.
Haza
rd R
ati
o
UK Nephrology, Bone and
Mineral Metabolism
Proteinuria & CVD Mortality
0
0.5
1
1.5
2
< 30 30 - 299 > 300
Haza
rd R
ati
o
Proteinuria mg/dL
Muntner et al., JASN 2002
UK Nephrology, Bone and
Mineral Metabolism
Cardiovascular Ossification & CKD
15% of children on dialysis
30% – 70% of CKD patients
Arterial dysfunction: Stiffness
Valvular disease
Conduction abnormalities
Mechanism is complex: Ca, P, vitamin D, PTH, inflammation, imbalance between promoters and inhibitors
UK Nephrology, Bone and
Mineral MetabolismBlacher J, Hypertension 2001
Calcification Score and Mortality
F/U Duration (Months)
Su
rviv
al
Pro
bab
ilit
y
UK Nephrology, Bone and
Mineral Metabolism
Lack of Physical Activity in CKD
P. Painter, Hemodialysis Int’l 2005
Ph
ysi
cal
Fu
nct
ion
Sca
le S
core
UK Nephrology, Bone and
Mineral Metabolism
“Renalism” is the aggressive management
of CKD patients because of their high risk
for cardiovascular disease.
A) True
B) False
UK Nephrology, Bone and
Mineral Metabolism
“Renalism”
Less ACEI/ARB – Fear of ↑K+ or AKI
Less ASA – Fear of bleeding
Less beta blocker – Fear of ?↑K+ or ↓pulse
Less angioplasty – Fear of radiocontrast
Less CABG - Fear of increased morbidity and
mortality
Post MI death was less likely if CKD patients received
acute reperfusion therapy, ASA or BB (each HR 0.7)Wright et al, Ann Intern Med 2002
The “New” Cardiorenal Syndrome
Adapted from: Stenvinkel et al.,
CJASN March 2008
Traditional
Risk Factors
Age, Male, HTN, Smoking, LVH,
DM, Dyslipidemia
Novel and Uremia-
Related Risk Factors
-Oxidative stress, inflammation
-Endothelial dysfunction
-Anemia
-Vascular calcification
-Coagulation disorders
-Atherosclerotic plaque
-Sympathetic activation
-Subclinical hypothyroidism
-Uremic bone disease
-Volume overload
-Protein energy wasting
-Insulin resistance
-Uremic toxins
-Adipokine imbalance
-Genetics/epigenetics
UK Nephrology, Bone and
Mineral Metabolism
Which of the following diabetic drugs
is/are contraindicated in CKD patients
with eGFR < 50 ml/min/1.73 m2?
A) Metformin
B) Glipizide
C) Glyburide
D) Sitagliptin
E) A & C
F) B & D
UK Nephrology, Bone and
Mineral Metabolism
Strategies to Reduce CVD Burden in CKD
Smoking secession
Exercise
Proper diet: Low Na, fat and phosphorus
BP control: < 130/80, ACEI/ARB, diuretics
Dyslipidemia control: LDL < 100 mg/dL, statins
Diabetes control: A1C < 7%, avoid metformin and glyburide
Anemia management: Hgb 11-12 g/dL
Mineral metabolism management
The Greek phosphorus is lucifer in Latin!
UK Nephrology, Bone and
Mineral Metabolism
Secondary Prevention of Small
Subcortical Strokes (SPS3) Study
Over 2800 patients
International, multicenters, NIH-sponsored
Two intervention strategies
Anti platelets therapy
Blood pressure control
Usual SBP arm (130-149) and intensive control (<130)
University of KY enrolled thus far 54 patients
Trial Registration: NCT00059306
NIH-NINDS (Grant #2 U01 NS38529-04A1).
UK Nephrology, Bone and
Mineral Metabolism
Achieving SBP <130 in SPS3 at UK
As of last visit (September 2010) Mean SBP 127 12; Median 125
36% SBP > 130
Mean follow up 42 months
Mean # of meds 3 1.6
Most common limiting factors to intensify therapy Side effects (BP-related, not class)
Fluctuation in BP
Dependency on home BP monitoring
UK Nephrology, Bone and
Mineral Metabolism
Treatment of CAD in CKD
Same as in non-CKD patients
Specific attention to drug dosing
Acute coronary syndrome
Therapies should include PCI, CABG, antiplatelet
agents, beta-blockers, thrombolytic therapy, and
lipid-lowering agents as indicated
Chronic CAD
Therapies should include ASA, beta-blockers,
nitroglycerin, ACEI/ARB, statins, and/or calcium-
channel blockers as indicated
K/DOQI Guidelines, AJKD 2005