EL PAPEL Y MANEJO DE LA DISLIPIDEMIA EN EL DAÑO

RENAL

Evidencia en la población general

Evidence from the General Population

0

20

40

60

80

100

120

140

<204 215 255 285 >295SERUM CHOLESTEROL (mg/dL)

CH

D

INC

IDEN

CE

per

1,0

00

FRAMINGHAM STUDY (n= 5,209) ‡

‡ W P Castelli Am J Med. 1984; 76:4

What are CHD Risk Equivalents

DiabetesChronic Kidney DiseaseOther clinical forms of

atherosclerotic disease:– Peripheral arterial disease (PAD)– Abdominal aortic aneurysm (AAA)– Carotid artery disease

Multiple ( single or total) risk factors that confer a 10-year risk for CHD > 20%

NCEP ATP III RECOMMENDATIONS JAMA 2001; 285

ATP III Recommendations

• Treatment should be started if LDL:– >100 mg/dL for CHD or CHD

equivalent (10-year risk > 20%)– >130 mg/dL for 2+ risk factors

(10-year risk 10-20%)– >160 mg/dL for 0-1 risk factor

(10-year risk < 10%)

NCEP ATP III RECOMMENDATIONS JAMA 2001; 285

WHY?

• LEFT VENTRICULAR HYPERTROPHY:– Eccentric: fluid retention,anemia,AVF– Concentric: HTN,Aortic valvular

disease

• ATHEROSCLEROSIS:– Occlussive vascular, Ischemic Heart

Disease and Increased Calcium deposition

• ARTERIOSCLEROSIS:– Loss of elasticity of the Aorta and

large vessels

Hay alguna diferencia entre la población general y los pacientes en hemodiálisis?

CVD in Hemodialysis Patients

0.001

0.01

0.1

1

10

100

25-34 35-44 45-54 55-64 65-74

HD

GP

An

nu

al M

ort

alit

y

(%)

AGE ( years)R. Foley, et al., Am J Kidney Dis 1998; 32 (Suppl 3)

Los pacientes con insuficiencia renal crónica

Dyslipidemia and CKD facts

Chronic Kidney Disease patients have 10-100 increased incidence of

death due to cardiovascular

complications compared with the general

population.

Foley et al., Am. Journal Kidney Diseases 1998; 32

Chronic Kidney Disease in the US

STAGE GFR(ml/min/1.732)

Prevalence

Prevalence (%)

1 ~ 90 5,900,000

3.3

2 60-89 5,300,000

3.0

3 30-59 7,600,000

4.3

4 15-29 400,000 0.2

5 <15 or dialysis

300,000 0.1CKD Guidelines. Am J Kidney Diseases 2002; 39 Suppl. 1

GENERAL CONCEPTS• Chronic Kidney Disease in the US:

– 20 MILLION patients with CKD– Defined as a sustained GFR < 60

ml/min/1.73 m2 or patients with microalbuminuria of > 30 mg/day

Cardiovascular disease is a modifiable risk factor

• In CKD : – low cholesterol is associated with

increased mortality– Statins can decrease –Δ GFR and

decrease the CRP

GENERAL CONCEPTS II

• Chronic Kidney Disease patients (CKD) lipid panel is characterized:– Decrease level of Apo A I + II

leading to LOW levels of HDL– Increased level of Apo B leading

to HIGH levels of LDL and VLDL

WHY

DECREASED LIPOLYTIC ENZYMES, POOR APOPROTEIN BINDING CAPACITY AND DECREASED UPTAKE OF LIPOPROTEINS

CKD and Cardiovascular Disease

• Traditional risk factors:– Diabetes

mellitus– Dyslipidemia– Hypertension

• Non Traditional risk factors:– Inflammation– Oxidative stress– Malnutrition– Proteinuria– Anemia– Volume excess– Abnormal Ca/P– Hyperhomocystein

emiaSarnak M J, et al. Cardiovascular disease and chronic renal disease:

a new paradigm. Am J Kidney Dis. 2000;35 (4 suppl 1)

Framingham

Lipids characteristics on CKD

• General population- increased LDL• CKD patients: No correlation with

LDL• Increased Lipoprotein a Lp (a) in

CKD• Hemodialysis patients have a

decreased catabolic rate for Lp (a)• Lp(a) and Apoprotein a are not well

treated by statins.Kronenberg F. Dyslipidemia. ASN November 2003 San Diego, California

PREVALENCE (%)Total

cholesterol

LDL HDL TG

mg/dL > 240 > 130

< 35 > 200

General population 20 40 15 15

CKD 1-4

Nephrosis 90 85 50 60

Nephritis 30 10 35 40

CKD 5

HEMO 20 30 50 45

Peritoneal 25 45 20 50

LIPID ABNORMALITIES

MORTALITY associated with Dyslipidemia

Lowrie at al., Am J Kid Disease 1990;15:458-482

REACTIVE OXIDATIVE SPECIES (ROS)

• Increased production of ROS at the endothelium- Increased LDL oxidation

• Oxidized LDL molecule is taken by macrophages leading to foam cells and calcification of the vessels

• ROS inactivate nitric oxide:– Promoting pro-atherogenic events:

• Increased WBC adherence•Platelet aggregation• Increasing CRP

Niwa et al. ASN November 2003 San Diego, California

MECHANISMS OF CELLULAR DAMAGE

Daño Tubular:Oxidaciónde LDL con efectoProfibrótico y deproliferación

Inflamación vascular causando aterosclerosis de vasos.

Endothelial cells Activation Hypertrophy

CELLULARHUMORAL

Antidonor Ab MФ T Cell

CD 8 T cellsPerforin positive

Cytolytic effectorpathway

Allogeneic arterial injury during AR

FibrogenesisRemodelingLipid trappingGround deposition

Cell transformation

Functional ActivationUpregulation of Class I & II MHC and Adhesion molecules:

More endothelial damageAb, complement,CTL Fas mediated apoptosis

Loss of Barrier with influx of: fibrin,platelets, LDL, RBC’s

Platelet DGF,FGF,IL-1, IL-6

IMMUNE MECHANISMS

ARTERY

Are there any special considerations for dyslipidemia

treatment in CKD ?

Strength of Evidence for Treating Dyslipidemias in CKD

CKD STAGE Strength of Evidence

1 (≥90) *****2 (60-89) ****3 (30-59) ***

4 (< 30) **5 Dialysis *5 Transplants

****

Therapy for Dyslipidemia

• Are the STATINS effective and safe to treat Dyslipidemia among CKD patients?

• Can we impact CARDIOVASCULAR mortality among CKD patients?

• Other benefits of STATINS beyond Cholesterol control?

Potential RenoprotectiveEffects of Statins

1. Mason JC. Curr Opin Nephrol Hypertens. 2005;14:17-24. 2. Jardine AG, Holdaas H, Fellstrom B, et al. Am J Transplant. 2004;4:988-995.

• Have been shown to provide pleiotropic effects independent of their proven beneficial effect on lowering cholesterol levels1

• Anti-inflammatory effects may be useful for the management of glomerulonephritis and diabetes mellitus

• May have a potential immunomodulatory role in organ transplant recipients2

• Have been shown to enhance endothelial function2

• Have antioxidant effects2

EFFICACY

• Peritoneal dialysis experience:– Study: 177 PD patients treated for 4

weeks with Atorvastatin– Experienced ↓ of LDL-C ↓ of TG and

significant of HDL-C compared to placebo arm. в Harris et al.,KI 2002;61

• Hemodialysis experience:– All studies have confirmed ↓ of LDL-C

є Van den Akker et al., Nephrol. 2003:16

• Renal Transplantation experience:– ALERT STUDY: 5 year follow up of 200

patients treated with fluvastatin experienced a 32% reduction in LDL-C ф

TREATMENT OVERVIEW

DYSLIPIDEMIA

(mg/dL)

GOAL INITIATE INCREASE

ALTERNATIVE

TG≥500 TG<500 Lifestyle changes

Lifestyle changes + fibrate or niacin

Fibrate or niacin

LDL-C 100-129

LDL-C <100 Lifestyle changes

Lifestyle changes and low dose statin

Bile acid sequestrant or niacin

LDL-C≥ 130 LDL-C <100 Lifestyle changes and low dose statin

Lifestyle changes and max-dose statin

Bile acid sequestrant or niacin

TG ≥ 200 and non-HDL-C ≥ 30

Non-HDL-C <130

Lifestyle changes and low dose statin

Lifestyle changes and max- dose statin

Fibrate or niacin

TABLE 2

TREATMENT OVERVIEW cont.

• FIBRATES:– Used to treat TG reducing by 30-50%– Fibrates are renal excreted– Increased risk of Rhabdomyolysis with statins– Increase serum creatinine

• NICOTINIC ACID:– Most efficacious increasing HDL-C– No studies in CKD patients

• BILE ACID SEQUESTRANTS:– Block intestinal reabsorption of bile acid and

LDL-C

PHARMACOLOGY & SAFETY

PHARMACOLOGY & SAFETY cont

• Most statins are metabolized by the liver.

• Get a baseline CPK• Myalgias: check CPK and hold

the statin•Restart at 50% of the dose or use

another•Consider use CoQ 10•Do not use in patients with acute or

chronic liver disease•Be careful with Calcineurin

Inhibitors, warfarin, grapefruit juice

Statin Dose Adjustment in CKDAdjust for ↓ GFR ?

AGENT

GFR

60-90 15-59 <15

AtorvastatinAtorv vs Prav (-36% vs -5.2% in CRP reduction)

NO NO NO

Fluvastatin ? ? ?Lovastatin NO ↓ to 50% ↓ to 50%Pravastatin NO NO NO

Simvastatin ? ? ?Rosuvastatin NO ↓ to 50% ↓ to 25%Am J Kidney Dis 2003; 41 Suppl 3

Other Dose Adjustments in CKD

Adjust for ↓ GFR ?

GFR AGENT

60-90 15-59 <15

Nicotinic acid NO NO ↓ to 50%

Cholestipol NO NO NO

Cholestyramine

NO NO NO

Cholesevelam

NO NO NO

Am J Kidney Dis 2003; 41 Suppl 3

Other Dose Adjustments in CKDAdjust for ↓ GFR

?GFR

AGENT

60-90 59-15 15

Bezafibrate

↓ to 50% ↓ to 25% Avoid

Clofibrate ↓ to 50% ↓ to 25% Avoid

Ciprofibrate

? ? ?

Fenofibrate

↓ to 50% ↓ to 25% Avoid

Gemfibrozil

NO NO NO

Am J Kidney Dis 2003; 41 Suppl 3

K/DOQ I GUIDELINES

NCEP- ATP III AJKD 2003; 41

MAIN DIFFERENCE IS TO KEEP LDL-C LESS THAN 100 mg/dL

Atorvastatin & CKD Progression

• Open label, randomized, controlled study

• 56 patients with idiopathic membranous glomerulonephritis– Proteinura > 1 g/24 hrs– All treated with ACEi for 1 year then:– Atorvastatin 40 mg vs. no treatment

• Outcome of Atorvastatin vs. control at 1 year:– Cr clearance: 49.8±1.7 vs. 44.2±1.5

mL/min (p<0.05)– Urine protein: 1.5 vs. 2.2 g/24 hrs

(p<0.01)S Bianchi, et al., Am J Kidney Dis 2003; 41:565

Dyslipidemia in Renal Transplant Recipients

Lipid Abnormality

% in Kidney Transplant Recipients

Total cholesterol: >240 mg/dL (6.21 mmol/L)

60%

LDL-C >130 mg/dL (3.36 mmol/L) 60%

Triglycerides 35%

HDL-C <35 mg/dL (0.9 mmol/L) 15%

Kasiske BL. Am J Kidney Dis. 1998;5(Suppl 3):S142-S146.Kasiske BL, et al. J Am Soc Nephrol. 1996;7:158-165.

NON-HDL CHOLESTEROL

PATIENT A PATIENT B

HDL

LDL

VLDL+IDL

200

CH

OLE

STER

OL

(mg/d

L)

TG 100 350VLDL +IDL 20 70LDL 140 90HDL 40 40Non-HDL 160 160

Am J Kidney Dis 2003; 41 Suppl 3

IMPROVEMENTS

• Chronic Kidney Disease Stages 2-4– CARE STUDY– Cholesterol and Recurrent Events– Randomized, double-blinded,

placebo contolled trial– 1,700 patients with crcl < 75

ml/min experienced a ↓ 28% in AMI and fatal CHD compared with the untreated group

Tonelli at al., Annals of Internal Medicine 2003;138:98-104

Lipid Lowering in CKD Patients in the Cholesterol and Recurrent Events (CARE) Study

4159 with AMI and cholesterol < 240 mg/dL

3384 with MDRD-calculated eGFR

690 with eGFR < 60 ml/min/1.73m2

MDRM eGFR(ml.min/1.73m2)

Slowing of GFR decline

(ml.min/1.73m2/year)

P-value

<60 0.1 0.49

<50 0.6 0.07

<40 2.5 0.001

M Tonelli, et al., J Am Soc Nephrol 2003;14:1605

IMPROVEMENTS

• CKD 5:– Selinger et al., KI 2002; 61– HMG CoA reductase inhibitors

are associated with reduced mortality in ESRD patients.

• RENAL Transplant Experience:– ALERT STUDY:– Tread toward ↓incidence of cardiac

death, non fatal MI and less coronary aa procedures on the Fluvastatin group vs. control.

OTHER STATINS EFFECTS

• Anti-inflammatory effects:– Decreased the levels of

atherogenic oxidazed LDL-C– ↓ C Reactive Protein

• Reducing Progression of CKD:– Statins can ↓ the –Δ GFR and

decrease the proteinuria

Kasiske B. et al., KI 2001; 59Tonelli et al., JASN 2003; 14Bianchi et al., AJKD 2003; 41

STATINS SIDE EFFECTS

•Liver function test abnormalities

•Rhabdomyolysis•Myalgias•Proteinuria

Statins and > 2+ ProteinuriaTREATMENT DOSE(m

g)N %

Rosuvastatin 5 587 0.2

10 1008 0.6

20 872 0.7

40 1850 1.2

Atorvastatin 10 628 0.5

20 438 0.5

40 63 0.0

80 342 0.3

Simvastatin 20 452 1.1

40 314 0.3

80 325 0.0

Pravastatin 20 163 0.6

40 34 0.0

Placebo --- 330 0.6

DG Vidt, et al.,Cardiol 2004; 102:52

OTHER STUDIES in the pipeline

• DIE DEUTSCHE DIABETES DIALYSE 4D:– Evaluated in a prospective, randomized,

placebo controlled trail- 1,200 HD /Type II DM pts on atorvastatin 20 mg/day

• SHARP:– The Study of Heart and Renal Protection– Prospective, randomized, placebo

controlled trail- 6,000 predialysis and 3,000 dialysis pts

– Plan is to evaluate the efficacy of Ezetimide and Simvastatin vs. placebo

• AURORA:– prospective, randomized, placebo

controlled trail- 3,000 HD patients on rosuvastatin

2007

Deutsche Diabetes-Dialyse-Studie

1

2

6

CU

MU

LATIV

E IN

CID

EN

CE O

F TH

E

PR

IMA

RY C

OM

PO

SIT

E E

ND

PO

INTS(%

)

60%

3

years

Atorvastatin vs.placebo

4-D Primary EndpointEndpoint Placebo

(n=636)

Atorvastatin

(n=619)

P-value

Primary 243(38%) 226(37%) 0.37Cardiac death

149(23%) 121(20%) 0.08

Non-fatal MI

79(12%) 70(11%) 0.42

Fatal stroke

13(2%) 27(4%) 0.04

Non-fatal stroke

32(5%) 33(5%) 0.89

C Wanner et al., N Engl J Med. 2005;353:238

CONCLUSIONS

• CKD PATIENTS ARE A CHALLENGE DUE TO THEIR COMPLEX MEDICAL PROBLEMS AND BECAUSE THE TREATMENT OF THEIR DYSLIPIDEMIA EVOLVES WITH THEIR DISEASE RAPID TURNOVER AND CHANGES

• THERE IS INSUFFICIENT DATA TO ASSESS THE USE OF THESE AGENTS USED TO TREAT DYSLIPIDEMIAS IN RENAL FAILURE PATIENTS.