CKD and CVD

• Jamal Salameh, MD, FACP, FASN

First Coast Nephrology

An Epidemic of Kidney Disease

Clinical Practice Guidelines for CKD Am J Kidney Dis. 2002;39(suppl 1):S17–S31.

GFR = glomerular filtration rate (mL/min/1.73 m2); *with kidney damage

Stage 1: GFR ≥90*

Stage 3: GFR 30–59

Stage 4: GFR 15–29

Stage 2: GFR 60–89*

Stage 5: GFR <15

n=5,900,000

n=5,300,000

n=7,600,000

n=400,000

n=300,000

Total=23 million USA

Prevalence CKD stages 1- 4

10% 1988-94

13% 1999-2004 Coresh, JAMA 298:2038, 2007

Scope of Disease: NHANES data

Figure 1.1 (Volume 1)

NHANES participants age 20 & older.

USRDS Annual Data Report 2011 Fig 1.1, Vol 1

CKD and CVD

• CKD is an independent risk for all types of CVD

• In addition, CKD is associated c adverse outcomes in patients c CVD

• This includes an inc M/M in CAD, PCI, CABG, PTA, CHF, PVD and arrhythmias (not discussed)

• Both a decrease in GFR and Proteinuria independently increase risk of CVD

KDIGO controversies conference KI 80:17-28, 2011

Albuminuria and GFR affect mortality and CKD outcomes

CKD predicts CV events: HOPE study

Mann et al. Ann Intern Med 2001;134:629–636

0

10

20

30

40 All patients

Patients taking placebo

Patients taking ramipril

Creatinine

<124 µmol/l Creatinine

≥124 µmol/l

n=8307

n=908 Events per

1000

person

years

HOPE=Heart Outcomes and

Prevention Evaluation study

Rates of death and cardiovascular events rise

as renal function declines

1.0

8 4.7

6

11

.36

14

.14

21

.8

36

.6

0.7

6

11

.29

3.6

5

2.1

1

0

10

20

30

40

>60 45-59 30-44 15-29 <15

Ag

e-s

tan

dard

ised

rate

per

100 p

ers

on

years

Death from any cause

Cardiovascular events

Go et al et al. NEJM 2004 23: 351(13): 1296-1305

Estimated GFR (ml/min/1.73 m2)

25-34 35-44 45-54 55-64 65-74 75-84 >85

Age

An

nu

al m

ort

ality

(%

)

Adapted from Levey AS et al. Am J Kidney Dis 1998; 32: 853-906.

Cardiovascular Mortality Rates are Higher among Dialysis Patients

General

population: male

General

population:

female

Dialysis: male

Dialysis: female

10

100

1

0.01

0.1

0.001

CKD and CVD

• Spectrum of disease:

-CAD (Angina/ACS)

-CHF

-CVA

-PVD

-SCD (Sudden Cardiac Death)

Prevalence of Co-morbidity and Level of GFR

%

GFR 60 ml/min

GFR <60 ml/min

DM CHF Stroke/

TIA

PVD Any

CVD

IHD

0

5

10

15

20

25

30

35

40

GFR 60

GFR< 60

CKD and CAD

• Incidence/Severity of CAD inc c dec GFR

• In pts c CAD, CKD worsens prognosis

• Pattern of Diffuse Multivessel dz

• Incidence approaches or > 50% in ESRD pts

• M/M are Inversely assoc c Dec GFR

• Typical Risk Factors are common in CKD

Cardiovascular diseases in CKD

patients

Damage to the heart

(Uremic cardiomyopathy)

Damage to the

arteries

(Uremic arteriopathy)

CKD and CAD

• Typical Risks include:

-Age (>55 M and >65 F)

-Sex (Male)

-Dyslipidemia (Inc LDL, Low HDL)

-Smoking

-FHx of CAD

CKD and CAD

• Traditional Risk Factors for CAD

-HTN

-DM

-LVH

-Sedentary Lifestyle

-Menopause

-Obesity

CKD Screening in the Primary Care Population: Who is “At Risk”

National Kidney Foundation Kidney Disease Outcome Quality Initiative: • NKF KDOQI • Provides evidence-based

clinical practice guidelines

CKD and CAD

• Non Traditional Risk Factors for CAD:

-Albuminuria

-Hyperhomocysteinemia

-Anemia

-Abnl Ca and PO4 metabolism-Vasc Ca++

-ECF Overload

-Inflammation

-Lipoprotein abnormalities

Cardiovascular Disease in CKD : Multifactorial Pathogenesis

Cardiovascular

Disease Chronic

inflammation

Exogenous

vitamin

D/deficit

Oxidative

stress

Duration of

dialysis Elevated PTH/

2°HPT

Hypertension

Dyslipidemia

Diabetes

Mellitus

Genetics

Increased homocysteine

levels

Elevated Ca ×

P product

Exogenous Ca

intake

Hyperphos-

phatemia

Smoking

Traditional risk factors

Non Traditional risk factors

Patients New to Dialysis and Established Patients

Prevalence of Vascular Calcification in CKD

40%

57%

83%

0%

20%

40%

60%

80%

100%

Russo et al RIND TTG

*Russo et al AJKD 2004 (CrCl =33 ml/min) **Spiegel D et al. Hemod Internat 2004: 8:265 ***Chertow et al KI 2002

*

**

***

Stage 3-4 CKD

Probability of All-Cause Survival According to Calcification Status

*Comparison Between Curves Was Highly Significant (x2=42.66, P<0.0001)

Source: Blacher A, et al. Hypertension:938-942, October 2001

Pro

bab

ilit

y o

f S

urv

ival

0.00

0.25

0.50

0.75

1.00

Duration of Follow-Up (Months)

0 20 40 60 80

Calcification Score: 0

Calcification Score: 1

Calcification Score: 2

Calcification Score: 3

Calcification Score: 4

Serum Phosphorus and Mortality

in Hemodialysis Patients

1.50

1.00 1.00 1.08

1.25

1.42

1.68

2.03

0

0.5

1

1.5

2

2.5

<3 3-4 4-5 5-6 6-7 7-8 8-9 >9

Serum Phosphorous Concentration (mg/dL)

Rela

tive R

isk o

f D

eath

*

n = 40,538

P < 0.0001

*Multivariable Adjusted Block G, J Am Soc Neph 15: 2208-2218, 2004

CKD and CAD

CKD and CAD

CKD and CAD

• Treatment:

-ASA

-Clopidogrel

-B Blockers

-ACE I/ARB’s

-Statins (not much data in ESRD x SHARP)

-PCI

-CABG (Conflicting data re PCI vs CABG)

CKD and CHF

• CHF Increases c Declining GFR

• CHF is Leading CV condition in CKD

• Common etiologies are Pressure/Volume XS

• Myocardial Interstitial Fibrosis (RAAS/SNS/Endothelin/ADH/TGF/IL1/TNF..)

Synergistic effect of CKD, CHF and Anemia as risk factors for Death

Collins, Adv studies in Med 2003

2 yr mortality (n~ 200,000 5% Medicare sample)

%

CKD and CHF

CKD and CHF

• Treatment:

-Na restriction

-Diuretics (usually higher doses) and UF

-ACE I/ARB’s

-BB (Carvedilol, Metoprolol, Bisoprolol)

-Anemia Tx

-Ca and Phos Tx to prevent Calcifications

CKD and CVA

• Independent risk for ICH and Ischemic-RR=1.4

• ESRD pts have a 5-10 risk of age match population to equal approx 4%/year

• Most CVA ischemic 87% in CHOICE study (enrolled 78% ESRD pts and rest CKD 5)

• Approximately 33% during or just p HD

• Mortality approx 35%, much higher than non

HD population, compared to 12% for CKD only

CKD and CVA

• Treatment:

-Tx HTN

-Antiplatelets

-Statin rx (controversy in ESRD x SHARP)

-CEA in ipsilateral high grade dz

CKD and PVD

• CKD independent risk factor for PVD

• NHANES reported prevalence of 24% in CKD

• Other studies report 7% to 48% prevalence

• Worse stage/GFR yields worse dz

• High rate traditional risk factors in CKD pts

• Nontraditional risk factors abound too

CKD and PVD

• Treatment:

-Antiplatelets

-Smoking cessation

-Plavix not studied in CKD population

-Cilostazol helped in ESRD pts

-Statins (as discussed prior)

-PTA vs Bypass (ESRD pts may?? do better c

PTA)

CKD and SCD

• SCD defined as sudden death, unexpected

within an hour of Sx onset

• Accounts for 25% of death in ESRD pts

• Annual rate of 5.5% per year

• Survival is quite poor at 3-11% at 6 mos

• SCD incrementally increases c decreasing GFR

• ESRD pts die from SCD > ACS

• CKD pts die from ACS > SCD

Epidemiology of SCD : CKD populations

• CKD stages 3-5 (not dialysis) SCD risk ↑ by HR of 1.1 for every 10ml/min decline in eGFR

• Event rate 0.8% per yr in non-dialysis CKD

• In non-diabetic dialysis patients, rate is 7% in 1st yr of RRT

• SCD risk is > for HD than PD patients during 1st 6 months of dialysis, but equalizes thereafter

0

10

20

30

40

50

60

70

eventrate per1000 yrs

General

CKD

Dialysis

Karnik JA et al (Kidney International 2001:60:350-357) : Characteristics associated with arrest on hemodialysis

– Monday or Tuesday (greatest risk last 12 hrs before dialysis)

– Low potassium dialysate – Older age – Diabetic – Catheter for access

CKD and SCD

• In ESRD pts Inc in SCD p long interHD periods

• Causes (?Hyperkalemia, ?Fluid XS, ?Low K/Ca baths)

• High prevalence of CMO, LVH, Hyperkalemia, Fluid Overlad and Long QT

• Treatment: BB and AICD all not studied well

0

10

20

30

40

50

60

70

80

50-75 25-50 <25 Dialysis

Creatinine clearance (mL/min)

Pre

vale

nce o

f L

VH

(%

)

p <0.003 (trend

analysis)

Prevalence of Left Ventricular Hypertrophy in Relation to Creatinine Clearance

Patients with diabetes = 24%

Adapted from Levin A et al. Am J Kidney Dis 1999; 34: 125-34.

n = 246

CKD and CVD

• In Conclusion there is paucity of data here

• ESRD pts are usually excluded from trials

and have a high mortality over a short time

frame complicating our ability to study and

recruit these most vulnerable pts

• Thus the Txs for non ESRD pts should be used

for ESRD pts and further work is needed

Cumulative probability of a physician visit at month 12 after CKD

diagnosis, by dataset & physician specialty: all CKD Figure 3.5 (Volume 1)

Medicare (age 66 & older)

& MarketScan & Ingenix i3

(age 50–64) patients with

CKD identified in 2007.

CKD patients are receiving most of their care from their PCP

USRDS Annual Data Report 2011

Timely Referral Leads to Reduced

Mortality

0%

10%

20%

30%

40%

On

e Y

ea

r M

orta

lity

Ra

te

< 1 month 1-4 mos > 4 mosTiming of Referral to

Nephrologist

(Time Prior to Start of

Dialysis)

Impact of Timing of Referral to

Nephrologist on Mortality

Early Referral Late Referral

90 Day Mortality 3 3% 13%

6 Month Mortality 4 13% 31%

1 Year Mortality 5 6% 39%

1 Year Mortality 2 22% 41%

2 Year Mortality 6 56% 69%

2

5

In a Recent Study of 300 Medicare Beneficiaries,

the Risk of Death in the First Year on Dialysis

Was Reduced by 48% For Early Referral

Patients Compared to Late Referral Patients. 2

Several Other Studies Shown Below Confirm

This.