hmghmg--coa reductase inhibitors and coa reductase ... · hmghmg--coa reductase inhibitors and coa...

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

Vito M. Campese, MDVito M. Campese, MD

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

< 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

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

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

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))

≥60 45–59

30–44

15–29

<15 ≥60 45–59

30–44

15–29

<15 ≥60 45–59

30–44

15–29

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

–– 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

vent p=0.006

Risk Reduction: 25%

Months

0 12 24 36 48

p=0.002Risk Reduction: 28%

Doubling of Serum CreatinineDoubling of Serum Creatinine

Months0 12 24 36 480 12 24 36 48

vent p=0.006

Risk Reduction: 25%

ESRDESRD

Months

0 12 24 36 480 12 24 36 48

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

ESRD or Death

P (+ CT)L (+ CT)

Months

0 12 24 36 480

751 714 625 375 69762 715 610 347 42

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

0 12 24 36 480

751 714 625 375 69762 715 610 347 42

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

–– 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?

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

–– 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

–– 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

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

–– 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

280 or more240 to 279200 to 239170 to 199<170

Total-C (mg/dL)

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

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

Total cholesterol (mg/dL)

>260220-260

<189 189-2200.0

LDL-cholesterol (mg/dL)

>167137-167

<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

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

�� 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

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

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

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.

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

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%)

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.

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

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

BaselineBaseline 1212 2424 3636 4848 6060

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

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

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.

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

0 1 2 3 4 5 6Time (years)

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.

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

Atorvastatin 10 mg (n=3324)

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

0 1 2 3 4 5 6Time (years)

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

* 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

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?

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

�� 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

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

>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

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

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

The percentage

Run-In Phase Study Phase

The percentage decline in urine protein excretion (UPE) was significantly greater in patients treated with atorvastatin than in those not treated (P <0.01)

-12 -6 0 3 6 9 12

-57.2%Urin

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

-11.1%*

Run-in Phase Study Phase

The percentage declinein creatinine clearance

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

-12 -6 0 3 6 9 12

-19.5%*

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

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

Foam cellsAltered

vascular tone

Oxidized LDL

Increasedmatrix

production

Mesangialcell

proliferation

Increasedglomerularpressure

Glomerulosclerosis

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)

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

Sham STNx +atorvastatin

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

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

AT 1-R EGF-R

p22phox

Ang II

PLDPKC

p47phox

Activation of the NADPH Oxidase by Ang II

AT 1-R EGF-R

p22phox

Ang IIStatins

PLDPKC

p47phox

RacGDP

RacGEF

Is There Experimental Evidence That Statins Potentiate the Renal

Protective Effects of

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

• 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

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

/d) 800

mo after disease induction in PHN rats

4 mo(before treatment)

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

10 mo after disease induction in PHN rats

4 mo(before treatment)

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

Tubular DamageGlomerulosclerosis

% Score

• Combination of statin and ACEI significantly limited:

– glomerulosclerosis

– tubular damage

– interstitial inflammation

10 months4 months(before treatement)

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

�� 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

–– 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 !!

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

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

hmghmg--coa reductase inhibitors and coa reductase ... · hmghmg--coa reductase inhibitors and coa...

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