cardiovascular risk in chronic kidney disease dr ginny quan

Cardiovascular Risk In Chronic Kidney Disease

Dr Ginny Quan

Who Shall Live ?

NBC documentary screened in the 70’s, USA

Cardiovascular Risk In Chronic Kidney Disease

Chronic Kidney Disease

• Persistent Renal Damage on Biopsy or Imaging

• Persistant abnormal urinalysis• Glomerular Filtration Rate

<60mL/min/1.73m2

CHRONIC KIDNEY DISEASE

Increased risk of Increased Risk of

CARDIOVASCULAR DISEASE

Cardiovascular Risk In CKD

1.Is it important?2.What factors are responsible? 3.What can be done about

them?

0

10

20

30

40

50

60

Lif

e ex

pect

ancy

in y

ears

25- 30- 35- 40- 45- 50- 55- 60-

Age in years

Dialysis patientsTransplant patientsGeneral population

Data from USRDS 2002 and USA National Vital Statistics Report 1999

Patients with End Stage Renal Disease

Die Young

What Do Patients with Renal Disease Die Of ?

UK renal registry 2002

What Do People With ERF Die Of ?• Cardiac death slightly increased compared to the general

population

BUT

• Age related risk for Cardiac death is very differentx200 age 25-29x5 age 80-84

Early CKD Predicts Risk of Cardiovascular Disease

HOORN Study:

•Population based cohort, n=631

•Age 50-75 yrs

•Followed 10.2 yrs

•5ml/min drop in GFR increased risk of CV death by 26%

Early CKD Predicts Risk of Cardiovascular Disease

0

10

20

30

40

50

60

Even

ts p

er 1

000 p

erso

n

yea

rs

creatinine<124 creatinine124-200

Outcomes catagorised by renal disease in HOPE

cardiovasculardeath

primaryoutcome

HOPE study : Patients at high risk of cardiovascular events. Mann JF Ann Intern Med 2001 134:629-36

6.6% 11.4%

15.1%

22.1%

P<0.001

P<0.001

Early CKD Predicts Risk Of Cardiovascular Disease

The hazard ratio for renal dysfunction in the HOPE study was as high as that conferred by diabetes

Microalbuminuria/Proteinuria Predicts Risk of Cardiovascular

Disease

• Predicts CV risk in DM

• Predicts CV mortality in general population- PREVEND increase in cardiovascular mortality of 1.35 for

each doubling of urinary albumin excretion

• Predicts CV risk in patients with other high risk factors- HOPE, Linear association between microalbuminuria and

an increased risk of endpoint


• Cardiovascular risk increases as soon as chronic kidney disease can be measured

• As renal function deteriorates risk of cardiovascular disease increases proportionally

• In ESRD cardiovascular risk up to 200 times the general population

• CKD associated with poorer outcome post cardiovascular events

Is It Important ?

• Prevalence diagnosed CKD estimated at 5554 pmp (0.5%)

• >80% will not develop ESRD

• Majority of these will die of CVD

• Population screening studies estimate up to 10% population with CKD



them?

What factors are responsible?

Risk factor Prevalence on starting dialysis

Prevalence in general population

Diabetes 54% 15%

Hypertension 96% 44%

LVH (ECG) 22% 3%

Low HDL cholesterol <40mg/dl

46% 28%

High triglycerides >200mg/dl

38% 23%

High tot cholesterol >240 mg/dl

15% 27%

High LDL cholesterol >160mg/dl

9% 26%

Longenecker JC :The CHOICE study J Am Soc Nephrol 2002 ;13;1918

1. Increased Prevalence of Conventional Risk Factors


2. Non-conventional risk factors

•Cardiac disease is atypical in CKD

•CKD is a risk factor for Cardiovascular disease independent of known risk factors

Cardiac Disease is Atypical in Renal Disease

General population:• Cardiac death mostly

due to Coronary Heart Disease

• 5% Have LVH on Echo

• Coronary artery calcification unusual

ESRD:• Cardiac death often

due to Cardiomyopathy /arrhythmia/CHF

• 75% Have LVH on Echo

• High incidence of coronary artery calcification


3. Lack of risk factor modification• Failure to recognise early CKD as a risk

factor for cardiovascular disease• Lack of trials in CKD patients• Fear of polypharmacy and side effects

in patients with severe renal disease

Risk Factors for Cardiac Disease In

CKD

Conventional

HypertensionDyslipidaemiaSmoking Diabetes

?Under treatment

Kidney related

AnaemiaCalcium metabolismVascular complianceFluid shiftsHomocysteine levelsInflammation (CRP)

?Under treatment

LVH



them?

What should go in a cardiovascular polypill for renal patients ?


CKD

Conventional


Kidney related


LVH

LVHAn independent risk factor for CHD in the general population and in renal disease.

CONCENTRIC LVH

Prevalence of LVH in HD patients

Foley et al, KI 1995;47:186-192

Echo findings predict survival in HD patients

Parfrey P et al. NDT. 1996;11:1277-85

0 6 12 18 24 30 36 42 48 54 60 66 72

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Months

Normal

Eccentric LVH

Concentric LVH

Systolic dysfunction

Surv

ival

LVH Develops Early in Renal Disease

LVH on echo found in:

• 30% with creatinine clearance 50-75ml/min

• 50% with creatinine clearance <25ml/min

Levin A Am J Kidney Disease 1999 34 125-34

LVH and Myocardial Dysfunction

Risk factors for LVH:

• Hypertension is treatable

• Anaemia is preventable and treatable– >95% of patients will respond to Epo

Treatment of Hypertension leads to LVH regression in the General

Population

Regression of LVH in hypertension-

meta analysis of 39 trials

Treatment of Hypertension leads to regression of LVH in

ESRD• LVH shown to regress with:

– Treatment of hypertension in ESRD – Treatment of hypertension in Chronic renal

failure– Treatment of anaemia in ESRD

• Regression of LVH in one study associated with improved cardiac outcomeFoley RN; J Am Soc Nephrol 2000


CKD

Conventional


?Under treatment

Kidney related


?Under treatment

LVH

Cardiovascular Disease and Hypertension in the general

population

• Cardiovascular risk increases progressively as blood pressure increases

• ? Threshold: relationship holds for blood pressures above 110/75

• Treating blood pressure <140/90 or lower reduces cardiovascular mortality and morbidity

.

CHD Mortality Related to Blood Pressure

Early renal failure estimated to increase diastolic blood pressure 10-20mmHg if untreated

Cardiovascular Disease and Hypertension in CKD

• ESRD– BP>140/90 associated with increased cardiovascular risk– Duration of hypertension prior to dialysis correlates with

mortality

• CKD– Subgroup analysis hypertension greater cardiovascular risk

factor than general population

• No major trials looking at reduction cardiovascular risk with BP reduction in renal patients

BUT • Biggest reduction in general population is evident in subgroups

– Other risk factors/Underlying target organ damage

HOT Study: 51% RR Reduction of CV Events in Diabetics

Hansson L et al. Lancet. 1998;351:1755-1762.

0

5

10

15

20

25

90 85 80

Major cardiovascular events/1,000 patient-years

p=0.005 for trend

mm HgTarget Diastolic Blood Pressure

Hypertension in Renal Disease-The size of the problem

• CKD– 50-90% hypertensive depending on stage

/disease– Around 50% not adequately controlled ie

>140/90

• ESRD– 80% of ESRD patients have hypertension– 50%-70% DO NOT achieve BP<130/80

Treating Hypertension in Renal Disease Has Other Massive

Advantages• Lowering blood pressure slows

progression of renal disease– Bp reduced from 130/80 to 125/75 reduces

decline in GFR by 10.2ml/min/yr -6.7ml/min/yr (mdrd trial)

• In renal disease aim for– <125/75 with proteinuria– <130/80 without proteinuria

Which Antihypertensive Is Best For Renal Protection?

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80

0 6 12 18 24 30 36

MONTHS

DO

UB

LIN

G O

F

CR

EA

TIN

INE

(%)

PLACEBO +antihypertensives

CAPTOPRIL +antihypertensives

1993 Lewis EJ

Treatment of Hypertension leads to LVH regression in the General

Population

Regression of LVH in hypertension-

meta analysis of 39 trials

Ramipril reduces cardiovascular endpoints in patients with mild renal

impairment

0

5

10

15

20

25

30

35

40

Eve

nts

per

100

0 p

erso

n

year

s

creatinine<124 creatinine>124

Cardiovascular Death

All patients

Patients takingplacebopatients takingramipril

Mann JF Ann Intern Med 2001 134:629-36

Summary: Recommendations for BP

Control in Renal disease• If target organ damage (Renal+proteinuria)

– Aim for BP<125/75

• If possible ACE first line

• On haemodialysis renal association standards – pre-dialysis <140/90– post-dialysis <130/80


CKD

Conventional


?Under treatment

Kidney related


?Under treatment

LVH

Degree of Anaemia predicts survival of patients on dialysis

0%

5%

10%

15%

20%

25%

30%

Hb11-12 Hb 10-11 Hb 9-10 Hb<9

Ma JZ; J Am Soc Nephrol 1999 Mar;10(3):610-9.

Incr

ease

d r

isk

of

death

Treatment of anaemia prior to ESRD

Evidence now for correcting anaemia prior to dialysis:– Patients feel better– Reduces LVH– Improves survival after starting dialysis

• 4800 patients followed prospectively after starting dialysis• EPO given prior to starting improved survival afterwards

Fink J Am J Kidney Dis 2001 Feb;37(2):348-55

Summary: Treatment of Anaemia

• Treat anaemia with recombinant EPO otherwise Hb stabilises at 7.0g/dl in CRF– £5000 per patient/year

• Treat early-Anaemia can first develops at a GFR <30ml/min (creatinine of 200umol/l)

• Target Hb >11g/dl


CKD

Conventional


?Under treatment

Kidney related

Anaemia

Calcium metabolismVascular complianceFluid shiftsHomocysteine levelsInflammation (CRP)

?Under treatment

LVH

Coronary Artery Disease is Atypical in Renal Disease

Coronary Artery Disease is Atypical in Renal Disease

• Dialysis patients age 20-30yrs – 88% of dialysis patients had some coronary

artery calcification– 5% of controls

• Coronary Artery calcification related to:– Length of time on dialysis– Calcium -phosphate product– Daily dose of calcium

Goodman WG Engl J Med 2000 May 18;342(20):1478-83.

Coronary Calcification In Renal Patients

In CKD/ESRD AIM TO:• Normalise phosphate• Reduce parathyroid hormone levels • Avoid hypercalcaemia

UNTIL RECENTLY OPTIONS LIMITED:• Aluminium binders –long term toxicity• Calcium binders-risk of hypercalcaemia /metastatic

calcification• Vitamin D (alphacalcidol)-risk of hypercalcaemia and

hyperphosphataemia

Coronary Calcification In Renal Patients

New phosphate binder-Sevelamer • Not absorbed• Lowers lipids • May halt progression of coronary calcification• Initial trials suggest mortality benefit (DCOR)

New Vit D compounds –Paricalcitol• Reduce PTH levels • Minimal increase in calcium and phosphate

Calcimimetics-Cinacalcet• Stimulates calcium receptor • Lowers PTH without increasing calcium and phosphate


CKD

Conventional

Hypertension

DyslipidaemiaSmoking Diabetes

?Under treatment

Kidney related


?Under treatment

LVH

Graded Correlation Between Plasma Cholesterol and

Coronary Risk in the general population

0

0.5

1

1.5

2

2.5

3

3.5

4

2.5 3.9 5.2 6.5 7.8

plasma cholesterol mmol/l

Cor

onar

y ri

sk r

atio

Six yr coronary risk in men age 35-37 screened for MRFIT studyStamler J JAMA 1986 256;2823

Reduction in Total and LDL cholesterol reduces coronary events

25-35% coronary events shown in all trials

• Almost all trials used statins

• Reduction shown in primary and secondary prevention

1-2mmol/l LDL, risk 25-40%

What Happens To Lipids In Renal Disease?

• Initially: – Rise in LDL cholesterol – Fall in HDL Cholesterol– Rise in triglycerides

• Endstage:– Total Cholesterol normal/low – LDL /HDL remains abnormal

All Changes Begin Early In Renal Disease

•? Intersection of the risks of malnutrition/inflammation and the risks of CHD

The relationship with cholesterol and CHD is atypical

in ESRD

There Are No Trials Showing Cholesterol Lowering Works in

Renal DiseaseTrial Primary or

secondaryprevention

Relativecoronary risk

reduction

Exclusion of renaldisease?

WOSCOPS Primary 31% YesCr >1.75mg/dl

AFCAPS/TEXcaps

Primary 34% YesNephrotic syndrome

CARE Secondary 24% YesRenal disease

LIPID Secondary 24% YesRenal Disease

4S Secondary 34% 1% had mild renal imp

Treatment of Hyperlipidaemia is Based on an Assessment of RiskTen Year Coronary Risk Cholesterol/LDL

GoalDrug

Very highRisk>30%

Previous CHDor equivalent

<5mmol/l or<3mmol/l, 25%?As low as poss

YES

High Risk15-30%

2 + risk factors <5mmol/l or<3mmol/l, 25%

YES ifnecessary

Low Risk<15%

1/0 risk factors ? NOLifestyle

Joint British Societies

How Should Renal Patients be Assessed?

• Epidemiologically renal patients at high risk– most ESRD >30% 10yr risk of CHD

BUT

• CHD is atypical in renal failure – Does cholesterol have the same significance?

Trials of cholesterol lowering in renal disease now beginning

TRIAL PATIENT NO

PATIENT TYPE

DRUG RESULT DUE

SHARP 9000 Esrd and CKD Simvastatin and ezetimide

2009

AURORA 2700 HD Rouvastatin 2008

4D 1252 HD/type II diabetes

Atorvastatin 2005

ALERT 2102 Transplant Fluvavstatin 2003

Statins May Also Slow Disease Progression

• Trials suggest statins may reduce the rate of progression to renal impairment

• ? Secondary to cholesterol lowering

• ? Secondary to separate anti-inflammatory effects

Summary: Recommendations for Now

40% will be high risk for other reasons

• UK guidelines for high risk group– LDL < 3.0mmol/l or Total cholesterol < 5.0mmol/l

• NKF recommends Controlling the epidemic of CV disease in CRD 1998 – Renal dysfunction: highest risk group for coronary events– Aim for LDL<2.5mmol/l using statin

• No specific recommendation from Renal Association Standards

In Conclusion

• Renal patients die of cardiac disease at a young age

• Increased risk is present as soon as renal dysfunction is measurable

• Due to:– Increased incidence of traditional risk factors– Other renal related factors

• Strategies to decrease excessive cardiac death in renal patients should begin early

In a renal cardiac polypill I would put….

• ACE/ARB • Other antihypertensives to achieve BP

lower than 130/80• Epo once Hb below 11.0• Statin if cholesterol >6.0 or if >5.0 and

other risk factors• ?Aspirin dependent on other risk factors

I WOULD BEGIN TREATMENT OR AS SOON AS CKD WAS IDENTIFIED


CKD

Conventional


Kidney related


LVH

UNDERTREATMENT

Meta-analysis of lipid lowering studies in CRF

• Statins most effective in lowering LDL cholesterol/total cholesterol

• Increased risk of myopathy

• Rhabdomyolysis (pain+CK>x10) almost always with drug combinations

Massey Kidney Int 1995

Homocysteine

• High homocysteine levels associated with an increased cardiovascular risk in general population

• Homocysteine levels increased in CRF

• No evidence that treating homocysteine levels make a difference

• If treating: folate /B12 /B6• But to have an effect in renal failure may need

high doses – eg 15mg folic acid (B6 100mg/day B12 1mg/day) did not

normalise levels

Homocysteine

• High homocysteine levels associated with an increased risk of cardiovascular disease Homocysteine not as important as hypercholesterolemia, smoking, diabetes mellitus, and hypertension

• Homocysteine levels increased in CRF• Observational data links homocsyteine to cardiovascular

disease in ESRD• No evidence that treating makes a difference• If treating 5mg /day in CRF or if levels of >30umol/l +B12

and B6• But studies suggest that to have an effect in renal failure

may need higher dose eg 15mg folic acid (B6 100mg/day B12 1mg/day) even then did not normalise levels

Patients with Renal Disease Die Young

UK renal registry 2002

cardiovascular risk in chronic kidney disease dr ginny quan

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