peter sawaya, md, facp, fasn professor of medicine ... · uk nephrology, bone and mineral...

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


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


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


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


Ad

just

ed H

R f

or

Dea

th

**

*


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”


Mineral Metabolism

CKD and CVD Risk FactorsNHANES III, N = 15,800

0%

20%

40%

60%

80%

100%

120%

Normal 60-89 30-59 <30


Foley et al., Mayo Clinic Proc 2005

% >

2 R

isk

Fact

ors

Smoking, Obesity, HTN, Hypercholesterolemia,

CRP, HgbA1C, Homocysteine, Anemia, UP/C


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


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


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


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


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


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


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 %


Mineral Metabolism

LV Fibrosis

A picture is worth a thousand words!

Normal Fibrosis


Mineral Metabolism

LV Fibrosis in ESRD Patients and

Risk of Death

Aoki et al., KI 2005

Multivariate Analysis

Fibrosis >30% = HR 27.1*


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


Mineral Metabolism

Sudden Cardiac Death

0

20

40

60

80

Hemodialysis Peritoneal Dialysis

% of Cardiac Deaths % of All-Cause Mortality

USRDS 2006


Mineral Metabolism

Adapted from GM London,

Seminars in Dialysis, 2003

Cardiac Remodeling

Hypertrophy Fibrosis

Pressure/Volume

Overload

Sympathetic

/ RAAS

Local

Factors Inflammation


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


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

(%

)


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


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


Mineral Metabolism

“The Micro Uremic Milieu”


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


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


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


Mineral Metabolism

Uridine Adenosine Tetraphosphate

(Up4A)

Endothelium-derived

Potent vasoconstrictor

Nonpeptidic

Accumulates in renal failure

Jankowski et al.,

Nature Medicine 2005


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


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


Mineral Metabolism

ADMA & CV Events

Adapted from:

Kielstein et al., AJKD 2005

Zoccali et al., Lancet 2001

Plasma ADMA

Ha

zard

Ra

tio


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


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


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


Mineral MetabolismBlacher J, Hypertension 2001

Calcification Score and Mortality

F/U Duration (Months)

Su

rviv

al

Pro

bab

ilit

y


Mineral Metabolism

Lack of Physical Activity in CKD

P. Painter, Hemodialysis Int’l 2005

Ph

ysi

cal

Fu

nct

ion

Sca

le S

core


Mineral Metabolism

“Renalism” is the aggressive management

of CKD patients because of their high risk

for cardiovascular disease.

A) True

B) False


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


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


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!


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).


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


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

peter sawaya, md, facp, fasn professor of medicine ... · uk nephrology, bone and mineral...

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