Renal Function in Cardiovascular Disease:

New Understandings

Renal Function in Cardiovascular Disease:

New Understandings

Hypertension: Treatment and control ratesPatients treated* Patients controlled on treatment

to <140/90 mmHg*

Per

cen

tag

e

100

80

60

40

20

0

JNC-V. Arch Intern Med 1993; 153: 154–183JNC-VI. Arch Intern Med 1997; 157: 2413–2449

1971–1972 1974–1975 1976–1980 1988–1991 1991–1994*For 1971–1972 and 1974–1975 hypertension is defined as levels 160/95 mmHg

Hypertension and end-organ function

Persistently elevatedblood pressure

Left ventricularhypertrophy

Coronary heartdisease

Heart failureEnd-stage renal disease

Stroke

0

5

10

15Male Female

Hypertension and left ventricular hypertrophy

Presence of hypertension(160/95 mmHg or on

antihypertensive therapy)

Increase in systolicblood pressure of 20 mmHg

Incr

ease

in

lef

t ve

ntr

icu

lar

mas

s/h

eig

ht

(g/m

)

Levy D et al. Ann Intern Med 1989; 110: 101–107

****

*

*p<0.05; **p<0.01

0 5 10 15 20

Hypertension

Normal

Hypertension and heart failure

Females

Males

Biennial age-adjusted rate of heart failureby hypertensive status per 1,000

Kannel WB. Am J Cardiol 1996; 77: 6B–11B

RR=3.0

RR=4.0

Hypertension, coronary heart disease and stroke

Rel

ativ

e ri

sk o

f C

HD

or

stro

ke4.00

2.00

1.00

0.50

0.25

76 84 91 98 105Approximate mean usual diastolic blood pressure (mmHg)

Stroke

CHD

MacMahon S et al. Lancet 1990; 335: 765–774

0

3

6

9

12

Hypertension and renal damageA

nn

ual

in

cid

ence

of

hyp

ercr

eati

nem

ia p

er 1

,000

Diastolic blood pressure (mmHg)

Whelton PK et al. J Hypertens 1992; 10(Suppl): S77–S84

90–104 105–114 115

Renal impairment: Prevalence

The progression of renal impairment can lead to end-stage renal disease which has huge medical, social and financial consequences

End-stage renal disease is particularly prevalent in:– The elderly

– African-Americans

– Patients with diabetes

Nearly half of the hypertensive population displays some abnormality of renal function

Early hypertrophy of renal tissue and increased glomerular filtration rate (GFR)

Development of glomerular lesions without any clinically appreciable disease (GFR remains increased)

Incipient nephropathy with microalbuminuria (GFR normal or slightly increased)

Clinical nephropathy with marked proteinuria and decreased GFR

GFR continues to decrease and end-stage renal disease develops

In type 1 diabetes, progression to end-stage renal disease has been sequenced into five stages:

Progression to end-stage renal disease

Measurement of GFR as a marker of renal disease

Endogenous creatinine Exogenous markers

Serumcreatinine

Creatinineclearance

Inulin Radioisotopes

51Cr-EDTA

99Tc-DTPA

125I-iothalamate

Serum creatinine and creatinine clearance: Normal values

Moore MA et al. Am Fam Physician 1992; 45: 1248–1256

2.0

1.5

1.0

0.5

0.0

150

125

100

Ser

um

cre

atin

ine

(mg

/dl)

Cre

atin

ine

clea

ran

ce (

ml/

min

)Male Female Male Female

Serum creatinine level of 1.4 mg/dl:What is the renal function?

Ser

um

cre

atin

ine

(mg

/dl)

12

10

8

6

4

2

0

Large muscular maleNormal maleSmall female

120 60 30 15

Fraction of normal renal function (%)Sica DA. Unpublished data

100 50 25 0

GFR (ml/min)

Calculating creatinine clearance

urinary creatinine concentration (mg/dl) x volume (ml)

plasma creatinine concentration (mg/dl) x time (min)

or

140 – age (years) x weight (kg) x 0.85 (for women)

72 x serum creatinine (mg/dl)

Cockroft DW et al. Nephron 1976; 16: 31–41

Urinary albumin excretion

Mogensen CE et al. Lancet 1995; 346: 1080–1084

Clinical proteinuria>300 mg/24 hrs (>200 µg/min)

Microalbuminuria30–300 mg/24 hrs (20–200 µg/min)

Normal excretion<30 mg/24 hrs (<20 µg/min)

Microalbuminuria: Prevalence and predictive power in diabetics

Type 1 diabetes

– Prevalence: 50%

– Predictive value for the development of nephropathy: 75%

Type 2 diabetes

– Prevalence: 25–60% (depending on ethnic origin)

– Predictive value for the development of nephropathy: 25%

Savage MW et al. Br J Hosp Med 1995; 54: 429–435Viberti GC et al. In: International Textbook of Diabetic Medicine, 1992

Microalbuminuria: Prevalence and predictive power in non-diabetics

Non-diabetics

– Prevalence: 25–40% (depending on level of antihypertensive control)

– Predictive value for the development of nephropathy: Thought to be lower than in diabetic patients

Bigazzi R et al. Nephron 1992; 61: 94–97Ljungman S. Am J Hypertens 1990; 3: 956–960

Therapeutic options in hypertension

Hypertension

ACE inhibitors

Calcium antagonists

Angiotensin IIantagonists

-blockers

1-antagonists

Diuretics

Therapeutic options in heart failure

Task Force of the ESC. Eur Heart J 1997; 18: 736–753

ACE inhibitorsDigoxin

Digitoxin

Diuretics

Indicated for the symptomatic

treatment of heart failure when fluid

overload is present

Indicated when a fast ventricular rate in atrial fibrillation is present in

any degree of symptomatic heart

failure due to systolic dysfunction

Indicated in all stages of symptomatic heart failure due to systolic

dysfunction, irrespective of

presence or absence of signs of volume

overload

Heart failure

The RAS and ACE inhibition

Angiotensinogen

Angiotensin I

Angiotensin II

Bradykinin

Inactive kininfragments

ACE Non-ACEenzyme

Serinepeptidase

Renin

ACE inhibitors in hypertension and heart failure

In hypertension, ACE inhibitors

Lower blood pressure

Reduce the progression of end-organ damage

In heart failure, ACE inhibitors

Improve cardiovascular hemodynamics

Improve symptomatolgy and exercise capacity

Decrease morbidity and mortality

Fosinopril improves symptomatology in heart failure

Dyspnea

Fatigue

Paroxysmal nocturnaldyspnea

Placebo

Fosinopril

–40 –20 0 20 40 60 80

Worsened (%) Improved (%)

Brown EJ et al. Am J Cardiol 1995; 75: 596–600

Fosinopril prevents worsening of heart failureE

ven

t ra

te (

%)

25

20

15

10

5

0

Placebo

Fosinopril

Supplementary Supplementary Hospitalization Withdrawaldiuretic diuretic or

emergency room visit

Erhardt L et al. Eur Heart J 1995; 16: 1892–1899

* **

* ***

*p=0.002 vs. placebo; **p=0.001 vs. placebo; ***p<0.001 vs. placebo

ACE inhibitors and renal impairment: Considerations

Occasional cases of renal impairment and hyperkalemia

have been reported with ACE inhibitors

Dose modifications are a consideration in

patients with renal impairment (except

for fosinopril)

ACE inhibitors show renoprotective

effects over and above blood

pressure control

ACE inhibitors

Adrenergic agents and renal impairment: Considerations

Post-dose temporary reduction in renal

blood flow and GFR

Modification of initial dosing is a consideration for

hydrophilic -blockers

There is no evidence of renoprotective effects over and

above blood pressure control

Adrenergic agents

Calcium antagonists and renal impairment: Considerations

The effect of renal impairment on

metabolism of some active metabolites of calcium antagonists

(e.g. diltiazem, verapamil) is

unknown

There is no evidence of a class-specific

renoprotective effect over and above blood pressure

control

Calcium antagonists

Diuretics and renal impairment: Considerations

Efficacy may be reduced in renal

impairment

Thiazides may decrease renal

blood flow and GFR

There is no evidence of renoprotective effects over and

above blood pressure control

Diuretics

Antihypertensive treatment in diabetes: Additional considerations

Adapted from Cziraky MJ et al. Ann Pharmacother 1996; 30: 791–801

Glucoseintolerance

Hyper-lipidemia

Insulinresistance

1-antagonists 0

ACE inhibitors

-blockers

Calcium antagonistsVerapamil/diltiazemNifedipine

00/

00

0/0/

DiureticsThiazidesIndapamide

0

0

0

Fosinopril can improve the lipid profile in diabetic patients

Ch

ang

e fr

om

bas

elin

e

7

6

5

4

3

2

1

0Total LDL Plasma

cholesterol cholesterol lipoprotein(a)(mmol/l) (mmol/l) (mg/dl)

Schlueter WA et al. Am J Cardiol 1993; 72: 37H–44H

Placebo

Fosinopril

*p<0.05 vs. placebo

*

*

*

Schematic diagram of ACE inhibition and renal function

Normotensive

Hypertensive

Hypertensive treatedwith an ACE inhibitor

Ren

al f

un

ctio

n (

%)

Time (years)

Renoprotection: ACE inhibitors vs. other antihypertensives

Calcium antagonists ACE inhibitors Diuretics and/or -blockers

Urinary protein

Mean systemic blood pressure

0 –10 –20 –30 –40 –50

Decrease from baseline (%)Böhlen L et al. Am J Hypertens 1994; 7: 84S–92S

ACE inhibitors are renoprotective

Patients with type 2 diabetes

Patients with type 1 diabetes

Non-diabetic patients with nephropathy

Non-diabetic patients with hypertension and nephropathy

Non-diabetic hypertensive patients without pre-existing nephropathy

ACE inhibitors have demonstrated renoprotective potential in:

ACE inhibition: Renoprotection in type 2 diabetes

Init

ial

valu

e o

f re

cip

roca

l cr

eati

nin

e (%

) 105

100

95

90

85

800 1 2 3 4 5 6 7

Treatment (years)

Ravid M et al. Arch Intern Med 1996; 156: 286–289

ACE inhibitor (years 1–5) and placebo (years 6 and 7)

ACE inhibitor (years 1–7)

Placebo (years 1–5) and ACE inhibitor (years 6 and 7)

Placebo (years 1–7)

ACE inhibition: Renoprotection in type 1 diabetes

PlaceboCaptopril

50

40

30

20

10

0

Die

d o

r n

eed

ed d

ialy

sis

or

tran

spla

nta

tio

n (

%)

0 1 2 3 4Follow-up (years)

Placebo n=202 198 192 186 171 121 100 59 26Captopril n=207 207 204 201 195 140 103 64 37

Lewis EJ et al. N Engl J Med 1993; 329: 1456–1462

p=0.006

ACE inhibition: Renoprotection in non-diabetic nephropathy

Pat

ien

ts n

ot

reac

hin

gan

en

dp

oin

t (%

)

100

90

80

70

60

500 1 2 3

Treatment (years)

Adapted from Maschio G et al. N Engl J Med 1996; 334: 939–945

PlaceboBenazepril

ACE inhibition: Renoprotection in hypertension and nephropathy

0 5 10 15 20 25 30 35

Hannedouche T et al. Br Med J 1994; 309: 833–837

Log rank test p<0.05

Treatment (months)

PlaceboACE inhibitor

Cu

mu

lati

ve s

urv

ival

rat

e (%

)

100

90

80

70

60

50

ACE inhibition: Renoprotection in hypertensive patients

Time (months)

0 6 12 18 24 30 360

–1

–2

–3

–4

–5

–6

–7

Dec

reas

e in

GF

R (

ml/

min

/1.7

3 m

2 )

Himmelmann A et al. Am J Hypertens 1996; 9: 850–853

ACE inhibitor

-blocker

Correlation between beneficial renal effects and albuminuria

Controls

ACE inhibitors

0.4

0

–0.4

–0.8

Ch

ang

e in

GF

R(m

l/m

in/1

.73

m2 /

mo

nth

)

Baseline albuminuria (mg/day)

<30 30–300 >300

Lebovitz HE et al. Kidney Int 1994; 45(Suppl 45): S150–S155

*

*p=0.02 vs. controls

Dual and compensatory drug elimination

If function of the liver is impaired, excretion

via the kidney increases

If function of the kidney is impaired, excretion via the liver increases

Elimination via the kidney and liver

PLUS

Dual and compensatory elimination

Elimination via the kidney and

liver ONLY

Dual elimination

0

20

40

60

80

100

Fosinopril: Renal clearance in patients with renal dysfunction

*Singhvi SM et al. Br J Clin Pharmacol 1988; 25: 9–16**Hui KK et al. Clin Pharmacol Ther 1991; 49: 457–467

Hepatic clearance

Renal clearance

None* Mild** Moderate** Severe**

Cle

aran

ce (

%)

Renal failure

Accumulation of lisinopril and enalapril in renal dysfunction

Sica DA et al. Clin Pharmacokinet 1991; 20: 420–427*p<0.05 vs. enalaprilat**p<0.001 vs. lisinopril

Fosinoprilat

Enalaprilat

Lisinopril

Accumulation index

***

1.0 1.5 2.0 2.5 3.0

Dosing of different ACE inhibitors depending on renal function

Creatinine clearance (ml/min)

<10 10–30 30–60 >60

Benazepril 2.5 mg/day 5 mg/day 10 mg/day 10 mg/day

Captopril Reduced Reduced 12.5 mgtwice/day

12.5 mgtwice/day

Enalapril 2.5 mg everyother day

2.5 mg/day 5 mg/day 5 mg/day

Fosinopril 10 mg/day 10 mg/day 10 mg/day 10 mg/day

Lisinopril 2.5 mg/day 5 mg/day 10 mg/day 10 mg/day

Quinapril Not determined 2.5 mg/day 5 mg/day 10 mg/day

Ramipril Not determined 1.25 mg/day 1.25 mg/day 2.5 mg/day

Sica DA. J Cardiovasc Pharmacol 1992; 20(Suppl 10): S13–S20

Simplifying antihypertensive treatment in the presence of renal failure

ACE inhibitors are the only antihypertensives with

established renoprotective potential

Hypertension accelerates the decline in GFR and many hypertensive patients have

some degree of renal impairment

If you consider treatment with an ACE inhibitor, consider dual and compensatory elimination

If some degree of renal dysfunction is found, consider treatment with an ACE inhibitor

Measure renal function

Consider that the patient may have renal impairment

If a patient presents with hypertension

WHY?

WHY?