54
HMG HMG-CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Renal Function Vito M. Campese, MD Vito M. Campese, MD 1 Vito M. Campese, MD Vito M. Campese, MD Professor of Medicine, Physiology and Biophysics Professor of Medicine, Physiology and Biophysics Chief, Division of Nephrology and Hypertension Center Chief, Division of Nephrology and Hypertension Center Keck School of Medicine, USC Keck School of Medicine, USC Los Angeles Los Angeles Berlin 21 Berlin 21-5-08 08

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

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Page 1: 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

Page 2: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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 >1.6-2.02.0<ESRD

Serum creatinine mg/dl

Page 3: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

Relationship Between Estimated GFR Relationship Between Estimated GFR (eGFR) and Clinical Outcomes(eGFR) and Clinical Outcomes

Death from Any CauseDeath from Any CauseTotal Events = 51, 424Total Events = 51, 424

Sta

ndar

dize

d E

vent

Rat

eS

tand

ardi

zed

Eve

nt R

ate

(per

100

Per

son

(per

100

Per

son

--Y)

Y)

Cardiovascular EventsCardiovascular EventsTotal Events = 139,011Total Events = 139,011

Any HospitalizationAny HospitalizationTotal Events = 554,651Total Events = 554,651

10

12

14

16

25

30

35

40

100

120

140

160

3Go AS, et al. Go AS, et al. N Engl J MedN Engl J Med. 2004;351:1296. 2004;351:1296--1305.1305.

eGFR (mL/min/1.73 meGFR (mL/min/1.73 m 22))

Age

Age

--Sta

ndar

dize

d E

vent

Rat

eS

tand

ardi

zed

Eve

nt R

ate

(per

100

Per

son

(per

100

Per

son

≥60 45–59

30–44

15–29

<15 ≥60 45–59

30–44

15–29

<15 ≥60 45–59

30–44

15–29

<150

2

4

6

8

0

5

10

15

20

0

20

40

60

80

Page 4: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

Risk Factors for Progressive Kidney Risk Factors for Progressive Kidney DiseaseDisease

�� HemodynamicHemodynamic

–– HypertensionHypertension

–– Glomerular hyperfiltrationGlomerular hyperfiltration

–– Endothelial dysfunctionEndothelial dysfunction

�� NonNon--hemodynamichemodynamic–– RAASRAAS–– AldosteroneAldosterone–– SNS activitySNS activity–– DyslipidemiaDyslipidemia–– HyperglycemiaHyperglycemia

4

–– EndothelinEndothelin–– Cytokines (TGFCytokines (TGF ββββββββ, HGF, PAI, HGF, PAI--1, etc.)1, etc.)–– Oxidative stressOxidative stress–– ProteinuriaProteinuria–– Dietary protein intakeDietary protein intake–– Calcium and P metabolismCalcium and P metabolism–– Nephron endowmentNephron endowment–– AnemiaAnemia–– Ethnicity and genderEthnicity and gender–– Tobacco smokingTobacco smoking–– OthersOthers

Page 5: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

RENAAL: Primary ComponentsRENAAL: Primary ComponentsDoubling of Serum Creatinine

Months0 12 24 36 48

% w

ith e

vent p=0.006

Risk Reduction: 25%

0

10

20

30

P

L

ESRD

Months

% w

ith e

vent

0 12 24 36 48

0

10

20

30

p=0.002Risk Reduction: 28%

P

L

Doubling of Serum CreatinineDoubling of Serum Creatinine

Months0 12 24 36 480 12 24 36 48

% w

ith e

vent p=0.006

Risk Reduction: 25%

0

10

20

30

P

L

ESRDESRD

Months

% w

ith e

vent

0 12 24 36 480 12 24 36 48

0

10

20

30

p=0.002Risk Reduction: 28%

P

L

5Brenner BM, et al. N Engl J Med. 2001;345:861-869.

ESRD or Death

P (+ CT)L (+ CT)

Months

% w

ith e

vent

0 12 24 36 480

10

20

30

40

50

751 714 625 375 69762 715 610 347 42

P

L

p=0.010Risk Reduction: 20%

751 692 583 329 52762 689 554 295 36P (+ CT)

L (+ CT)

Months762 715 610 347 42751 714 625 375 69

P (+ CT)L (+ CT)

Months

ESRD or DeathESRD or Death

P (+ CT)L (+ CT)

Months

% w

ith e

vent

0 12 24 36 480

10

20

30

40

50

751 714 625 375 69762 715 610 347 42

P

L

p=0.010Risk Reduction: 20%

751 692 583 329 52762 689 554 295 36P (+ CT)

L (+ CT)

Months762 715 610 347 42751 714 625 375 69

P (+ CT)L (+ CT)

Months

P = placeboL = losartan

Page 6: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

Risk Factors for Progressive Kidney Risk Factors for Progressive Kidney DiseaseDisease

�� HemodynamicHemodynamic

–– HypertensionHypertension

–– Glomerular hyperfiltrationGlomerular hyperfiltration

–– Endothelial dysfunctionEndothelial dysfunction

�� NonNon--hemodynamichemodynamic–– RAASRAAS–– AldosteroneAldosterone–– SNS activitySNS activity–– DyslipidemiaDyslipidemia–– HyperglycemiaHyperglycemia

6

–– EndothelinEndothelin–– Cytokines (TGFCytokines (TGF ββββββββ, HGF, PAI, HGF, PAI--1, etc.)1, etc.)–– Oxidative stressOxidative stress–– ProteinuriaProteinuria–– Dietary protein intakeDietary protein intake–– Calcium and P metabolismCalcium and P metabolism–– Nephron endowmentNephron endowment–– AnemiaAnemia–– Ethnicity and genderEthnicity and gender–– Tobacco smokingTobacco smoking–– OthersOthers

Page 7: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

To what extent do To what extent do lipid abnormalities contribute to lipid abnormalities contribute to

the progression of the progression of kidney disease?kidney disease?

7

kidney disease?kidney disease?

Page 8: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

�� Dyslipidemia is commonly present in patients with Dyslipidemia is commonly present in patients with CKD, microalbuminuria, proteinuria, and especially CKD, microalbuminuria, proteinuria, and especially those with nephrotic syndrome. It is usually those with nephrotic syndrome. It is usually characterized by:characterized by:

–– Elevated total cholesterolElevated total cholesterol

Lipid Abnormalities in CKDLipid Abnormalities in CKD

8

–– Elevated total cholesterolElevated total cholesterol

–– Elevated TG Elevated TG

–– Low HDLLow HDL 22/HDL/HDL33

–– Elevated small LDL particlesElevated small LDL particles

–– Elevated lipoprotein(a)Elevated lipoprotein(a)

Page 9: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

Animal Models of LipidAnimal Models of Lipid--induced Renal Injuryinduced Renal Injury

�� DietaryDietary--induced hyperlipidemiainduced hyperlipidemia–– Rat, guinea pig, rabbitRat, guinea pig, rabbit

�� Genetic hyperlipidemiaGenetic hyperlipidemia–– Obese Zucker ratObese Zucker rat

9

–– Spontaneously hypertensive obese ratSpontaneously hypertensive obese rat

�� Secondary hyperlipidemiaSecondary hyperlipidemia–– Dahl saltDahl salt--sensitive ratsensitive rat

–– Remnant kidney modelRemnant kidney model

Keane WF, et al. Kidney Int. 1994;46:910-920.

Page 10: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

Dyslipidemia and Progression of Dyslipidemia and Progression of Kidney DiseaseKidney Disease

10

Epidemiological EvidenceEpidemiological Evidence

Page 11: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

The Physicians’ Health StudyThe Physicians’ Health Study

�� 4483 healthy men provided blood samples in 1982 4483 healthy men provided blood samples in 1982 and 1996and 1996

�� Outcome measuredOutcome measured

–– Elevated creatinine defined as ≥1.5 mg/dL Elevated creatinine defined as ≥1.5 mg/dL

11

–– Reduced estimated CrCl ≤55 mL/minReduced estimated CrCl ≤55 mL/min

�� After 14 years, 134 (3.0%) had elevated creatinine After 14 years, 134 (3.0%) had elevated creatinine and 244 (5.4%) had reduced CrCland 244 (5.4%) had reduced CrCl

Schaeffner ES, et al. J Am Soc Nephrol. 2003;14:2084-2091.

Page 12: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

The Physicians’ Health StudyThe Physicians’ Health Study

1.5

2.5

2.0

Odd

s R

atio

of C

r >1

.5

12

280 or more240 to 279200 to 239170 to 199<170

Total-C (mg/dL)

0

0.5

1.0

Odd

s R

atio

of C

r

Schaeffner ES, et al. J Am Soc Nephrol. 2003;14:2084-2091.

Page 13: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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<0.05; †P<0.001

N. of events 133 155 176 217 119 138 153 199

N. at risk 370 373 379 376 330 343 346 340

Hazard ratio

0.0

Total cholesterol (mg/dL)

1.0

0.5

>260220-260

1.0

<189 189-2200.0

LDL-cholesterol (mg/dL)

1.0

0.5

>167137-167

1.0

<111 111-137

Page 14: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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?

Page 15: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 16: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 17: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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?

Page 18: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

�� 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.

Page 19: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria
Page 20: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria
Page 21: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria
Page 22: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

4

6

8

Atorvastatin 10 mg

Atorvastatin 80 mg

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

P<0.0001

(↑↑↑↑ 5.6%)

(↑↑↑↑ 8.3%)

P<0.0001

Mea

n In

crea

se fr

om B

asel

ine

TNT

22

0

2

MDRD (mL/min/1.73 m 2) Cockcroft-Gault (mL/min)

Estimates of Glomerular Filtration Rates (eGFR)MDRD = Abbreviated Modification of Diet in Renal Di sease All increases from baseline were statistically sign ificant ( P<0.0001)

(↑↑↑↑ 1.2%)

(↑↑↑↑ 3.3%)

Mea

n In

crea

se fr

om B

asel

ine

n=4829 n=4827 n=4824 n=4820

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 presentedat: 2007 Annual Meeting of the World Congress of Nephrology; April 21-25, 2007; Rio de Janeiro, Brazil.

Page 23: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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<0.0001 for all comparisons of atorvastatin 80 mg vs 10 mg

-2

0

2

4

Mean changes from baseline with atorvastatin 10 mg and 80 mg at the final visit (LOCF) were +6.6% and +9.8% in CKD patients (P<0.0001), and +5.2% and +7.6% in patients with normal eGFR (P<0.0001)

MonthsMonths

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 presentedat: 2007 Annual Meeting of the World Congress of Nephrology; April 21-25, 2007; Rio de Janeiro, Brazil.

Page 24: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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<0.0001

24

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

*

P<0.0001

*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke

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

Page 25: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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.

Page 26: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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.

Page 27: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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 treatment–baseline renal function interaction

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

With CKDWithout CKD

Mea

n C

hang

e in

eG

FR

fr

om B

asel

ine

(mL/

min

/1.7

3 m

0.0

0.5

1.0

1.5

n=1395 n=1377 n=716 n=697

Page 28: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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 <60 mL/min/1.73 m 2

Page 29: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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?

Page 30: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

�� 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

–– <30 mg<30 mg 2%2%

–– 3030--300 mg300 mg --48%48%

–– >300 mg>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.

Page 31: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 32: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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.

Page 33: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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.

Page 34: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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.

Page 35: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

N = 56 patients

Optimal Care� ACEI, ARB, or both

� + meds ↓ BP <140/90 mm Hg

(BP at 1 yr: 133/84 mm Hg)

� Diet

– low sodium

– low protein

Optimal Care w/o Atorvastatin (n=28)

Optimal Care with Atorvastatin* (n=28)

Optimal Care

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

35

1 year

– low protein

– low cholesterol

– low fat

Group Demographics� 19 men, 9 women in each

� Similar BP, BMI, serum

lipids, and UPE after 1 yr

1 year

Primary efficacy end point:� Change in UPE� Change in CrCl

*Atorvastatin titrated to max of 40 mg to achieve LDL-C < 120 mg/dL or 40% decrease in LDL-C compared to baseline

Page 36: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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 <0.01)

-60

-50

-40

-30

-12 -6 0 3 6 9 12

-57.2%Urin

e P

rote

in E

xcre

tion

(% c

hang

e)

Months

-31.2%*

With atorvastatinWithout atorvastatin

**PP <0.01<0.01†PP<0.05<0.05

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

*†

Page 37: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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 <0.01<0.01

in creatinine clearanceis significantly greater in patients treated with atorvastatin than inthose not treated (P<0.01)

Page 38: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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.

Page 39: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 40: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 41: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

TGFTGF--ββ1 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.

Page 42: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

Simvastatin-mediated changes in angiotensin II type 1 receptor density

*P<0.05 vs. baseline

42

Kiliszek, et al. Coron Artery Dis. 18(3):201-9, 2007.

Page 43: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

Statins exert immunomodulatory and anti-inflammatory effects

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

Page 44: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

Activation of the NADPH Oxidase by Ang II

Nox

AT 1-R EGF-R

p22phox

Ang II

44

PLDPKC

p47phox

p47phox

Page 45: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 46: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

Is There Experimental Evidence That Statins Potentiate the Renal

Protective Effects of

46

Protective Effects of ACE-Inhibitors ?

Page 47: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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)

Page 48: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 49: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 50: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 51: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 52: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 53: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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

Page 54: HMGHMG--CoA Reductase Inhibitors and CoA Reductase ... · HMGHMG--CoA Reductase Inhibitors and CoA Reductase Inhibitors and Renal Function Vito M. Campese, MD 1 ... –– Proteinuria

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 !!