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EL PAPEL Y MANEJO DE
LA DISLIPIDEMIA EN EL
     DAÑO RENAL
Evidencia en la
población general
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;
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
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
Dislipidemia en el daño renal ok
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
Dislipidemia en el daño renal ok
Hay alguna
diferencia entre la
población general y
los pacientes en
hemodiálisis?
CVD in Hemodialysis Patients
                             100


                              10
     Annual Mortality (%)



                               1
                                                                              HD
                                                                              GP
                              0.1


                             0.01


                            0.001
                                    25-34   35-44   45-54    55-64    65-74
                                                       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          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
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
Dislipidemia en el daño renal ok
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)
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       LDL     HDL     TG
                         cholesterol
             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:
                          Oxidación
                          de LDL con efecto
                          Profibrótico y de
                          proliferación




 Inflamación vascular
causando aterosclerosis
 de vasos.
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
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 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.
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        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
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 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%
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
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
K/DOQ I GUIDELINES




                              MAIN DIFFERENCE IS TO KEEP LDL-C
                              LESS THAN 100 mg/dL
NCEP- ATP III AJKD 2003; 41
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
                                                          % 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.
NON-HDL CHOLESTEROL
   200
                                                           HDL
CHOLESTEROL




                                                           LDL
              (mg/dL)




                                                           VLDL+IDL




                        PATIENT A   PATIENT B
 TG
                            100         350
 VLDL +IDL
                             20          70
 LDL
                            140          90
 HDL
                             40          40
                                                Am J Kidney Dis 2003; 41 Suppl 3
 Non-HDL
                            160         160
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              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
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; 59
         Tonelli et al., JASN 2003; 14
         Bianchi et al., AJKD 2003; 41
STATINS SIDE EFFECTS

• Liver function test abnormalities
• Rhabdomyolysis
• Myalgias
• Proteinuria
Statins and > 2+ Proteinuria
 TREATMENT      DOSE(mg)    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
                                        DG Vidt, et al.,Cardiol 2004;
                                        102:52
 Pravastatin       20      163    0.6

                   40      34     0.0

   Placebo         ---     330    0.6
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
Deutsche Diabetes-Dialyse-Studie



                                  60%
PRIMARY COMPOSITE END POINTS(%)
CUMULATIVE INCIDENCE OF THE




                                                        Atorvastatin
                                                           vs.
                                                        placebo
                                            2
                                        1           3             6

                                                years
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
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.

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Dislipidemia en el daño renal ok

  • 1. EL PAPEL Y MANEJO DE LA DISLIPIDEMIA EN EL DAÑO RENAL
  • 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
  • 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
  • 9. Hay alguna diferencia entre la población general y los pacientes en hemodiálisis?
  • 10. CVD in Hemodialysis Patients 100 10 Annual Mortality (%) 1 HD GP 0.1 0.01 0.001 25-34 35-44 45-54 55-64 65-74 AGE ( years) R. Foley, et al., Am J Kidney Dis 1998; 32 (Suppl 3)
  • 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
  • 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
  • 19. PREVALENCE (%) Total LDL HDL TG cholesterol 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
  • 21. MORTALITY associated with Dyslipidemia Lowrie at al., Am J Kid Disease 1990;15:458-482
  • 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.
  • 41. NON-HDL CHOLESTEROL 200 HDL CHOLESTEROL LDL (mg/dL) VLDL+IDL PATIENT A PATIENT B TG 100 350 VLDL +IDL 20 70 LDL 140 90 HDL 40 40 Am J Kidney Dis 2003; 41 Suppl 3 Non-HDL 160 160
  • 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
  • 47. Statins and > 2+ Proteinuria TREATMENT DOSE(mg) 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 DG Vidt, et al.,Cardiol 2004; 102:52 Pravastatin 20 163 0.6 40 34 0.0 Placebo --- 330 0.6
  • 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.

Notes de l'éditeur

  1. 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.