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 >1.6-2.02.0<ESRD
Serum creatinine mg/dl
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
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
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
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
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?
�� 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)
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.
Dyslipidemia and Progression of Dyslipidemia and Progression of Kidney DiseaseKidney Disease
10
Epidemiological EvidenceEpidemiological Evidence
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.
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.
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
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<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.
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.
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.
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 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
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
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
–– <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.
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 <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
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.
*†
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)
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--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.
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.
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 !!