3. Evidence from the General Population
FRAMINGHAM STUDY (n= 5,209) ‡
140
120
100
CHD INCIDENCE
per 1,000
80
60
40
20
0
<204 215 255 285 >295
SERUM CHOLESTEROL (mg/dL)
‡ W P Castelli Am J Med. 1984;
4. What are CHD Risk Equivalents
Diabetes
Chronic Kidney Disease
Other 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
5. 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
6.
7. 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
12. 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
13. Chronic Kidney Disease in the US
STAGE GFR Prevalence Prevalence
(ml/min/1.732) (%)
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 300,000 0.1
dialysis
CKD Guidelines. Am J Kidney Diseases 2002; 39 Suppl. 1
14. 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
15. 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
16.
17. CKD and Cardiovascular Disease
• Traditional risk • Non Traditional risk
factors: factors:
– Diabetes mellitus – Inflammation
– Dyslipidemia – Oxidative stress
– Hypertension – Malnutrition
– Proteinuria
– Anemia
– Volume excess
Framingham
– Abnormal Ca/P
– Hyperhomocysteinemia
Sarnak M J, et al. Cardiovascular disease and chronic renal disease:
a new paradigm. Am J Kidney Dis. 2000;35 (4 suppl 1)
18. 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
22. 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
24. Daño Tubular:
Oxidación
de LDL con efecto
Profibrótico y de
proliferación
Inflamación vascular
causando aterosclerosis
de vasos.
25. HUMORAL CELLULAR
Antidonor Ab MФ T Cell
Endothelial cells Activation Hypertrophy Cell
transformation
ARTERY Allogeneic arterial injury during AR
Functional Activation
Upregulation of Class I &
II MHC and Adhesion CD 8 T cells
molecules:
Platelet DGF,FGF, Perforin positive
More endothelial
damage IL-1, IL-6
Ab, complement,
Cytolytic effector
CTL Fas mediated Fibrogenesis pathway
apoptosis
Remodeling
Loss of Barrier with
Lipid trapping
influx of: fibrin,platelets,
LDL, RBC’s
Ground deposition
IMMUNE MECHANISMS
26. Are there any special
considerations for
dyslipidemia treatment in
CKD ?
27. 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 ****
28. 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?
29. Potential Renoprotective
Effects of Statins
• 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
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.
30. 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
31. TREATMENT OVERVIEW
DYSLIPIDEMIA GOAL INITIATE INCREASE ALTERNATIVE
(mg/dL)
TG≥500 TG<500 Lifestyle Lifestyle Fibrate or niacin
changes changes +
fibrate or
niacin
LDL-C 100-129 LDL-C <100 Lifestyle Lifestyle Bile acid
changes changes and sequestrant or
low dose statin niacin
LDL-C≥ 130 LDL-C <100 Lifestyle Lifestyle Bile acid
changes and changes and sequestrant or
low dose max-dose statin niacin
statin
TG ≥ 200 and Non-HDL-C Lifestyle Lifestyle Fibrate or niacin
non-HDL-C ≥ 30 <130 changes and changes and
low dose max- dose
statin statin
TABLE 2
32. 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
34. 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
35. Statin Dose Adjustment in CKD
Adjust for ↓ GFR ?
AGENT
60-90 15-59 <15
GFR
Atorvastatin NO NO NO
Atorv vs Prav (-36% vs
-5.2% in CRP reduction)
Fluvastatin ? ? ?
Lovastatin NO ↓ to 50% ↓ to 50%
Pravastatin NO NO NO
Simvastatin ? ? ?
Rosuvastatin NO
Am J Kidney Dis 2003; 41 Suppl 3 ↓ to 50% ↓ to 25%
36. Other Dose Adjustments in CKD
Adjust for ↓ GFR ?
GFR 60-90 15-59 <15
AGENT
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
37. Other Dose Adjustments in CKD
Adjust for ↓ GFR ?
GFR 60-90 59-15 15
AGENT
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
38. K/DOQ I GUIDELINES
MAIN DIFFERENCE IS TO KEEP LDL-C
LESS THAN 100 mg/dL
NCEP- ATP III AJKD 2003; 41
39. 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
40. Dyslipidemia in Renal
Transplant Recipients
% in Kidney Transplant
Lipid Abnormality Recipients
↑ Total cholesterol: >240 mg/dL (6.21
60%
mmol/L)
↑ 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.
42. 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
43. 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 Slowing of GFR P-value
(ml.min/1.73m2) decline
(ml.min/1.73m2/year)
<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
44. 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.
45. 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; 59
Tonelli et al., JASN 2003; 14
Bianchi et al., AJKD 2003; 41
46. STATINS SIDE EFFECTS
• Liver function test abnormalities
• Rhabdomyolysis
• Myalgias
• Proteinuria
48. 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
2007 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
49. Deutsche Diabetes-Dialyse-Studie
60%
PRIMARY COMPOSITE END POINTS(%)
CUMULATIVE INCIDENCE OF THE
Atorvastatin
vs.
placebo
2
1 3 6
years
50. 4-D Primary Endpoint
Endpoint Placebo Atorvastatin P-value
(n=636) (n=619)
Primary 243(38%) 226(37%) 0.37
Cardiac 149(23%) 121(20%) 0.08
death
Non-fatal MI 79(12%) 70(11%) 0.42
Fatal stroke 13(2%) 27(4%) 0.04
Non-fatal 32(5%) 33(5%) 0.89
stroke
C Wanner et al., N Engl J Med. 2005;353:238
51. 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.
Editor's Notes
Hyperlipidemia is common among kidney transplant recipients. 1 This includes increased levels of the particularly atherogenic lipoprotein (a) and small, dense, low-density lipoprotein cholesterol (LDL-C). 2 Serum cholesterol levels have been shown to be an independent risk factor for graft failure and patient mortality as well as CVD. The National Kidney Foundation Task Force on Cardiovascular Disease recommends that kidney transplant recipients should be considered to be in the highest category of CVD risk, when applying the National Cholesterol Education Program guidelines for the treatment of dyslipidemias. 1. Kasiske BL. 1998;5(suppl 3):S142-S146. 2. Kasiske BL, et al. J Am Soc Nephrol . 1996;7:158-165.