HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Renal Function

Vito M. Campese, MDVito M. Campese, MD

1

Vito M. Campese, MDVito M. Campese, MDProfessor of Medicine, Physiology and BiophysicsProfessor of Medicine, Physiology and Biophysics

Chief, Division of Nephrology and Hypertension Cent erChief, Division of Nephrology and Hypertension Cent erKeck School of Medicine, USCKeck School of Medicine, USC

Los AngelesLos Angeles

Berlin 21Berlin 21--55--0808

The Prevalence of CKD in USAThe Prevalence of CKD in USAx millionx million

8

10

12

1.6 >

2

0

2

4

6

< 1.6 1.6-2.0 >2.0 ESRD

1.6 >1.6-2.02.01

.5

12

280 or more240 to 279200 to 239170 to 199

Predictors of Risk in the RENAAL Predictors of Risk in the RENAAL Study (EndStudy (End--stage Renal Disease)stage Renal Disease)

Hazard ratio

1.5

2.5

2.0

1.97

1.41

1.18

*

1.5

2.5

2.0

1.87

1.24

1.07

LDL-cholesterolTotal Cholesterol

13Appel GB, et al. Diabetes Care. 2003;26:1402-1407. *P

Evidence That Statins Inhibit the Evidence That Statins Inhibit the Progression of Kidney DiseaseProgression of Kidney Disease

Animal StudiesAnimal Studies

Human subjectsHuman subjects

Patients with hypertension, or dyslipidemia and Patients with hypertension, or dyslipidemia and normal kidney functionnormal kidney function

14

normal kidney functionnormal kidney function Patients with CKD: Do statins reduce proteinuria an d Patients with CKD: Do statins reduce proteinuria an d

CKD progression?CKD progression?

Statins Inhibit the Progression of Kidney Statins Inhibit the Progression of Kidney Disease in the Following Animal ModelsDisease in the Following Animal Models

5/6 nephrectomy in Sprague5/6 nephrectomy in Sprague--Dawley ratsDawley rats

Obese Zucker ratsObese Zucker rats

Dahl saltDahl salt--sensitive ratssensitive rats

Puromycin aminonucleosidePuromycin aminonucleoside

15

Puromycin aminonucleosidePuromycin aminonucleoside

Development of polycystic kidney disease in the Development of polycystic kidney disease in the Han:SPRD ratHan:SPRD rat

Ischemic renal failure in cholesterolIschemic renal failure in cholesterol--loaded ratsloaded rats

Treatment of Hyperlipidemia Reduces Treatment of Hyperlipidemia Reduces Glomerular Injury in 5/6 Nephrectomized RatsGlomerular Injury in 5/6 Nephrectomized Rats

15

20

25

30

%

16

0

5

10

15

Kasiske BL, et al. Circ Res. 1988;62:367-374.

ControlControl 5/6 Nx5/6 Nx 5/6 Nx + 5/6 Nx + clofibric clofibric

acidacid

5/6 Nx + 5/6 Nx + HMGHMG--CoA CoA reductase reductase inhibitorinhibitor

Evidence That Statins Inhibit the Evidence That Statins Inhibit the Progression of Kidney Disease Progression of Kidney Disease

Animal StudiesAnimal Studies

Human subjectsHuman subjects

Patients with hypertension, or dyslipidemia and Patients with hypertension, or dyslipidemia and normal kidney function or Stage 1normal kidney function or Stage 1 --3 CKD3 CKD

17

normal kidney function or Stage 1normal kidney function or Stage 1 --3 CKD3 CKD Patients with CKD: Do statins reduce proteinuria an d Patients with CKD: Do statins reduce proteinuria an d

CKD progression?CKD progression?

Only patients with complete renal data (both baseli ne and postOnly patients with complete renal data (both baseli ne and post--baseline creatinine measurements) were included in renal analysisbaseline creatinine measurements) were included in renal analysis

Paired serum creatinine samples from baseline and t he final study Paired serum creatinine samples from baseline and t he final study visit were used for MDRD and Cockcroftvisit were used for MDRD and Cockcroft--Gault estim ates of GFRGault estimates of GFR

TNT Study Design:TNT Study Design:Analysis of Renal FunctionAnalysis of Renal Function

OpenOpen--label label RunRun--inin

Screening Screening and Washand Wash--outout

DoubleDouble--blind Periodblind Periodn=n=79657965

BaselineBaseline

18

Atorvastatin Atorvastatin 10 mg10 mg

8 Weeks8 Weeks11--8 Weeks8 Weeks

Atorvastatin 10 mgAtorvastatin 10 mgLDLLDL--C Target: 100 mg/dL (2.6 mmol/L)C Target: 100 mg/dL (2.6 mmol/L)

Median FollowMedian Follow--up = 4.9 Yearsup = 4.9 Years

Atorvastatin 80 mgAtorvastatin 80 mgLDLLDL--C Target: 75 mg/dL (1.9 mmol/L)C Target: 75 mg/dL (1.9 mmol/L)n=3988n=3988

n=3977n=3977BaselineBaseline

Shepherd J, et al. Paper presented at: American College of Cardiology 2006 Scientific Sessions. Atlanta, GA. Shepherd J, et al. Paper presented at: American Heart Association 2006 Scientific Sessions. Chicago, IL. Shepherd J, et al. Poster presented at: 2007 Annual Meeting of the World Congress of Nephrology; April 21-25, 2007; Rio de Janeiro, Brazil.

4

6

8

Atorvastatin 10 mg

Atorvastatin 80 mg

Both HighBoth High-- and Lowand Low--dose Atorvastatindose AtorvastatinSignificantly Improved eGFRSignificantly Improved eGFR

P

LS m

ean

% c

hang

e fr

om b

asel

ine

eGF

RCKD patientsCKD patients

Atorvastatin 80 mgAtorvastatin 80 mgAtorvastatin 10 mgAtorvastatin 10 mg

Patients with normal eGFRPatients with normal eGFRAtorvastatin 80 mgAtorvastatin 80 mgAtorvastatin 10 mgAtorvastatin 10 mg

4

6

8

10

12

Percent Change From Baseline eGFR Percent Change From Baseline eGFR in TNT Patients by CKD Statusin TNT Patients by CKD Status

23

BaselineBaseline 1212 2424 3636 4848 6060

CKDCKD 31073107 30403040 29552955 28062806 26812681 22642264Normal eGFRNormal eGFR 65496549 63876387 62076207 59805980 57795779 50305030

LS m

ean

% c

hang

e fr

om b

asel

ine

P

0.20

Pro

port

ion

of p

atie

nts

with

maj

or

card

iova

scul

ar e

vent

*

0.15

Time to First Major Cardiovascular Event By Baselin e Time to First Major Cardiovascular Event By Baselin e CKD Status Irrespective of Treatment AssignmentCKD Status Irrespective of Treatment Assignment

CKD patients (n=3107)

Normal eGFR patients (n=6549)

Relative risk increase = 31.9%(Absolute risk increase = 2.7%)

HR = 1.35 (95% CI 1.18, 1.54)P

0.20

Pro

port

ion

of p

atie

nts

with

maj

or

card

iova

scul

ar e

vent

*

0.15

Time to First Major Cardiovascular Time to First Major Cardiovascular Event By TreatmentEvent By Treatment

Atorvastatin 10 mg (n=3324)

Atorvastatin 80 mg (n=3225)

Normal eGFRRelative risk reduction = 15%

CKD (Stages 3-4)Relative risk reduction = 32%(Absolute risk reduction = 4.1%)

HR = 0.68 (95% CI 0.55, 0.84)P = 0.0003

Atorvastatin 10 mg (n=1505)

Atorvastatin 80 mg (n=1602)

25

0 1 2 3 4 5 6Time (years)

0.10

0.05

0

Pro

port

ion

of p

atie

nts

with

maj

or

card

iova

scul

ar e

vent

*

Relative risk reduction = 15%(Absolute risk reduction = 1.4%)

HR = 0.85 (95% CI 0.72, 1.00)P = 0.049

Shepherd J, et al. Poster presented at: American Society of Nephrology. 2006.

SPARCL Renal Sub Analysis

OBJECTIVE

To investigate the effect of high-dose atorvastatin treatment on renal function in stroke patients with no known CHD Effect stratified by chronic kidney disease Effect stratified by chronic kidney disease

(CKD) and glycemic status at baseline To determine the risk of primary and

secondary cardiovascular end points in patients stratified by CKD status at baseline.

Effect of Atorvastatin on Renal

Function by CKD Status

p < 0.0001

p = 0.017AtorvastatinPlacebo

Mea

n C

hang

e in

eG

FR

(m

L/m

in/1

.73

m2 )

2.0

2.5

3.0

3.5

* ANOVA model of treatment, baseline renal function, and treatmentbaseline renal function interaction

Without CKD = eGFR 60 mL/min/1.73 m 2; With CKD = eGFR

Liver and Muscle

Adverse Events

Without CKD With CKD

Atorvastatin(n=1567)

Placebo(n=1552)

Atorvastatin(n=789)

Placebo(n=811)

Liver Enzymes, n (%)Two consecutive elevations Two consecutive elevations out of time range 20 (1.3) 7 (0.5) 10 (1.3) 1 (0.1)

Musculoskeletal AEsRhabdomyolysisMyopathyMyalgia

2 (0.1)6 (0.4)86 (5.5)

1 (0.1)4 (0.3)88 (5.7)

01 (0.1)43 (5.4)

2 (0.2)3 (0.4)52 (6.4)

Without CKD = eGFR 60 mL/min/1.73 m 2; With CKD = eGFR

In CKD patients, do statins reduce proteinuria In CKD patients, do statins reduce proteinuria and CKD progression?and CKD progression?

29

and CKD progression?and CKD progression?

Randomized, placebo controlled statin trials which included Randomized, placebo controlled statin trials which included baseline and follow up 24hr urine collection or albuminbaseline and follow up 24hr urine collection or albumin--toto--creatinine ratioscreatinine ratios

15 studies identified, with 1348 patients averaging 24 weeks in 15 studies identified, with 1348 patients averaging 24 weeks in duration, published studies were not of high qualityduration, published studies were not of high quality

MetaMeta--Analysis: Analysis: The Effect of Statins on AlbuminuriaThe Effect of Statins on Albuminuria

30

Statins reduced proteinuria, with greater reductions seen with Statins reduced proteinuria, with greater reductions seen with higher levels of baseline proteinuriahigher levels of baseline proteinuria

300 mg --47%47%

Statins may have a beneficial effect on pathologic proteinuriaStatins may have a beneficial effect on pathologic proteinuria

Douglas K, et al. Ann Intern Med. 2006;145:117-124.

Individual and pooled results of 15 randomized, plac ebo-controlled trials examining the effect of statins on albuminuria or p roteinuria, stratified by

baseline excretion

Douglas, K. et. al. Ann Intern Med 2006;145:117-124

A Controlled, Prospective Study of the A Controlled, Prospective Study of the Effects of Atorvastatin on Proteinuria and Effects of Atorvastatin on Proteinuria and

Progression of Kidney DiseaseProgression of Kidney Disease

32

Bianchi S, Bigazzi R, Caiazza A, Campese VMBianchi S, Bigazzi R, Caiazza A, Campese VM

Am J Kidney DisAm J Kidney Dis. 2003;41:565. 2003;41:565--570.570.

Effects of Atorvastatin on Proteinuria Effects of Atorvastatin on Proteinuria and Progression of Kidney Diseaseand Progression of Kidney Disease

To assess the effect of atorvastatin on the To assess the effect of atorvastatin on the progression of kidney disease in pts with CKD and progression of kidney disease in pts with CKD and proteinuria secondary to idiopathic proteinuria secondary to idiopathic glomerulopathiesglomerulopathies

56 pts with chronic glomerulonephritis (proteinuria 56 pts with chronic glomerulonephritis (proteinuria >1 g/24 h w/o known etiology)>1 g/24 h w/o known etiology)

Objective

Population

33

>1 g/24 h w/o known etiology)>1 g/24 h w/o known etiology)

Mean age 55.6 yr; mean BMI 27.6Mean age 55.6 yr; mean BMI 27.6

Baseline BP 144/93 mm Hg (27/56 were Baseline BP 144/93 mm Hg (27/56 were hypertensive)hypertensive)

Baseline lipids: Baseline lipids: TotalTotal--C 320 mg/dLC 320 mg/dL TG 215 mg/dLTG 215 mg/dL LCLLCL--C 189 mg/dLC 189 mg/dL HDLHDL--C 36 mg/dL C 36 mg/dL

Population

Bianchi S, et al. Am J Kidney Dis. 2003;41(3):565-570.

Baseline Clinical CharacteristicsBaseline Clinical Characteristics

Number of pts (M/F)Number of pts (M/F) 56 (38/18)56 (38/18)

Age (y)Age (y) 55.6 55.6 11

BMI (w/hBMI (w/h 22)) 27.6 27.6 0.260.26

Hypertension (yes/no)Hypertension (yes/no) 27/2927/29

Office SBP (mm Hg)Office SBP (mm Hg) 144.3 144.3 2.42.4 133.0 133.0 1.01.0

Start of 2nd YearBaseline

34

Office SBP (mm Hg)Office SBP (mm Hg) 144.3 144.3 2.42.4 133.0 133.0 1.01.0

Office DBP (mm Hg)Office DBP (mm Hg) 93.3 93.3 1.81.8 84.8 84.8 0.80.8

CrCl (mL/min)CrCl (mL/min) 55.5 55.5 1.41.4 50.4 50.4 1.31.3

UPE (g/24 h)UPE (g/24 h) 2.7 2.7 0.10.1 2.2 2.2 0.10.1

TotalTotal--C (mg/dL)C (mg/dL) 320 320 4.7 4.7 310 310 3.33.3

LDLLDL--C (mg/dL)C (mg/dL) 189 189 55 198 198 4.14.1

HDLHDL--C (mg/dL)C (mg/dL) 36.2 36.2 0.70.7 36.1 36.1 0.60.6

Serum albumin (g/dL)Serum albumin (g/dL) 3.35 3.35 0.060.06 3.30 3.30 0.060.06

Bianchi S, et al. Am J Kidney Dis. 2003;41(3):565-570.

N = 56 patients

Optimal Care ACEI, ARB, or both

+ meds BP

Effects of Atorvastatin on Proteinuria Effects of Atorvastatin on Proteinuria and Progression of Kidney Diseaseand Progression of Kidney Disease

The percentage

-20

-10

0

Urin

e P

rote

in E

xcre

tion

(% c

hang

e)

Run-In Phase Study Phase

36

The percentage decline in urine protein excretion (UPE) was significantly greater in patients treated with atorvastatin than in those not treated (P

Effects of Atorvastatin on Proteinuria and Effects of Atorvastatin on Proteinuria and Progression of Kidney DiseaseProgression of Kidney Disease

-10

-5

0

Cre

atin

ine

Cle

aran

ce

(% c

hang

e)

-11.1%*

Run-in Phase Study Phase

The percentage declinein creatinine clearance

37Bianchi S, et al. Am Journal Kid Dis. 2003;41:565-570.

-25

-20

-15

-12 -6 0 3 6 9 12

-19.5%*

Cre

atin

ine

Cle

aran

ce

(% c

hang

e)

Months

With atorvastatin

Without atorvastatin

**PP

Statins for Improving Renal Outcomes: A Meta-Analysis

27 studies with 39,704 individuals identified for e GFR analysis

Weighted mean differences for eGFR were statistical ly significant in favor of the statin treated populati on with a 1.22 mL/min/yr slower fall in GFR

38

a 1.22 mL/min/yr slower fall in GFR

Sandhu S, et al. J Am Soc Nephrol. 2006;17:2006-2016.

Mechanisms of Lipid InjuryMechanisms of Lipid InjuryMechanisms of Lipid InjuryMechanisms of Lipid Injury

Increased LDL

Macrophages

CytokinesGrowth factorsChemoattractansEicosanoids ROI

Mesangialcell

dysfunction

Alteredvasoactivesubstances

Endothelialcell

dysfunction

39

O2-

Foam cellsAltered

vascular tone

Oxidized LDL

Increasedmatrix

production

Mesangialcell

proliferation

Increasedglomerularpressure

Glomerulosclerosis

O2-

Mesangial cell injury

Inflammatory Chemokines:Inflammatory Chemokines:Effects of StatinsEffects of Statins Down regulation of:Down regulation of:

Mesangial production of monocyte chemotactic protei nMesangial production of monocyte chemotactic protei n--1 1 (MCP(MCP--1) 1)

MonocyteMonocyte--colony stimulating factor (Mcolony stimulating factor (M--CSF)CSF)

Vascular cell adhesion molecule (VCAM)Vascular cell adhesion molecule (VCAM)

Intracellular adhesion moleculeIntracellular adhesion molecule --1 (ICAM1 (ICAM--1)1)

40

Kim S-Y, et al. Kidney Int. 1995;48:363-371.

Intracellular adhesion moleculeIntracellular adhesion molecule --1 (ICAM1 (ICAM--1)1)

PlateletPlatelet--derived growth factors (PDGF)derived growth factors (PDGF)

Transcription of the nuclear factorTranscription of the nuclear factor--kB (NFkB (NF--kB), which plays a kB), which plays a major role in mesangial cell inflammatory responsemajor role in mesangial cell inflammatory response

Inhibition of:Inhibition of: Infiltration of monocytesInfiltration of monocytes

Proliferation of mesangial cells and interstitial f ibrosisProliferation of mesangial cells and interstitial f ibrosis

TGFTGF--1 Gene Expression in Subtotal 1 Gene Expression in Subtotal NephrectomyNephrectomy

41

Sham STNx +atorvastatin

STNx

Cooper ME et al. Kidney Int. 1999;Suppl 71:S-31.

Simvastatin-mediated changes in angiotensin II type 1 receptor density

*P

Statins exert immunomodulatory and anti-inflammatory effects

43Campese, et al. Kidney International. 71:1215-22, 2007.

Activation of the NADPH Oxidase by Ang II

Nox

AT 1-R EGF-R

p22phox

Ang II

44

PLDPKC

p47phox

p47phox

Activation of the NADPH Oxidase by Ang II

Nox

AT 1-R EGF-R

p22phox

Ang IIStatins

45

PLDPKC

p47phox

p47phox

Src

PI-3K

PIP3

RacGDP

RacGDP

RacGEF

Is There Experimental Evidence That Statins Potentiate the Renal

Protective Effects of

46

Protective Effects of ACE-Inhibitors ?

A Combination of Lisinopril and Statin Reduced BP More Than Any Single Drug

Both PHN animals and control exhibited an increase in SBP at end of the study

Treatment with an ACEI

PH

N180

170

160

150

Con

trol

PH

N +

veh

icle

PH

N +

lis

40

PH

N +

lis

400

PH

N +

sim

va

PH

N +

lis

40 +

sim

va

Con

trol

BP

(m

m H

g)

47

Treatment with an ACEI or a statin alone reduced SBP.

A combination of the two drugs reduced SBP more than any single drug

Zoja C et al. Kidney Int. 2002;61:1635-1645.

4 mo90

10 mo

100

110

120

130

150

140

BP

(m

m H

g)

A Combination of Lisinopril and Statin Reduced Proteinuria More Than Any Single Drug

UPE measured at 4 mo (before treatment) and 10 mo after disease induction

PH

N +

veh

icle

PH

N +

lis

40

PH

N +

lis

400

PH

N +

sim

va

PH

N +

lis

40 +

sim

va

Con

trol

PH

N +

veh

icle

PH

N +

lis

40

PH

N +

lis

400

PH

N +

sim

va

PH

N +

lis

40 +

sim

va

Con

trol

1000

Pro

tein

uria

(ng

/d) 800

48

mo after disease induction in PHN rats

Zoja C et al. Kidney Int. 2002;61:1635-1645.

Pro

tein

uria

(ng

/d)

4 mo(before treatment)

10 mo

800

600

400

200

0

A Combination of Lisinopril and Statin Improved Serum Creatinine More Than Any Single Drug

SCr measured at 4 mo (before treatment) and 10 mo after disease

PH

N

Con

trol

PH

N +

veh

icle

PH

N +

lis

40

PH

N +

lis

400

PH

N +

sim

va

PH

N +

lis

40 +

sim

va

Con

trol

SC

r (m

g/dL

)

2.5

3.0

2.0

49

10 mo after disease induction in PHN rats

Zoja C et al. Kidney Int. 2002;61:1635-1645.

4 mo(before treatment)

10 mo

SC

r (m

g/dL

)

0

0.5

1.5

1.0

A Combination of Lisinopril and Statin Reduced Kidney Damage More Than Any Single Drug

4

3

2

1

0

+

0

100

80

60

40

20

0#+

Tubular DamageGlomerulosclerosis

% Score

50

Combination of statin and ACEI significantly limited:

glomerulosclerosis

tubular damage

interstitial inflammation

Zoja C et al. Kidney Int. 2002;61:1635-1645.

00

4

3

2

1

0

0

10 months4 months(before treatement)

Score

10 months4 months(before treatement)Interstitial Inflammation

Overall SummaryOverall Summary

Lipid abnormalities contribute not only to increase d Lipid abnormalities contribute not only to increase d prevalence of CV disease but also to progressive lo ss of prevalence of CV disease but also to progressive lo ss of renal functionrenal function

There is a relationship between degree of hyperlipi demia There is a relationship between degree of hyperlipi demia and progressive renal diseaseand progressive renal disease

51

Treatment of hyperlipidemia in patients with nephro tic Treatment of hyperlipidemia in patients with nephro tic syndrome and/or renal insufficiency may reduce syndrome and/or renal insufficiency may reduce proteinuria and the rate of progression of kidney d iseaseproteinuria and the rate of progression of kidney d isease

Aggressive treatment of dyslipidemia in CKD patient s Aggressive treatment of dyslipidemia in CKD patient s potentially reduces the excess CV risk associated w ith potentially reduces the excess CV risk associated w ith CKDCKD

Overall SummaryOverall Summary

The beneficial effect of statins may be the direct The beneficial effect of statins may be the direct consequence of lipidconsequence of lipid--lowering, but it also may lowering, but it also may be due to pleotropic effects, such as:be due to pleotropic effects, such as:

Regulation of cellular proliferation/apoptosis balanceRegulation of cellular proliferation/apoptosis balance

Reduction of inflammatory cytokines and oxidative Reduction of inflammatory cytokines and oxidative

52

Reduction of inflammatory cytokines and oxidative Reduction of inflammatory cytokines and oxidative stressstress

Involvement in intracellular signaling pathwaysInvolvement in intracellular signaling pathways

Improvement of endothelial functionImprovement of endothelial function

TakeTake--Home Message Home Message (Opinion(Opinion--based)based)

LipidLipid--lowering drugs should be used to reduce lowering drugs should be used to reduce proteinuria and CKD progression !!proteinuria and CKD progression !!

53

ThankThankThankThank----you you you you for your for your for your for your

54

for your for your for your for your attention !!attention !!attention !!attention !!