Dyslipidemia and CKD - sltung.com.t · 2017-03-20 · Assessment of Lescol in Renal Transplant (ALERT) study • Multicenter, randomized, double-blind, placebo-controlled trial •

血脂異常與慢性腎病

簡孝文醫師腎臟科

童綜合社團法人童綜合醫院100年8月28日

Outline

• Chronic kidney disease• Lipid metabolism and dyslipidemia• Renal dyslipidemia • Impacts of dyslipidemia on CV outcome• Impacts of dyslipidemia on renal outcome• Take home message

• An association between lipid abnormalities and the pathogenesis of renal disease was first suggested in 1860 by Virchow

• Virchow described extensive fatty metamorphosis in renal autopsy tissue obtained from patients with Bright’s disease

Outline


CKD staging and prevalence

National Kidney Foundation AJKD 39(suppl 1): S1-266, 2002

Equations to calculate GFR

40歲之後: GFR每年減少0.75 ml/min

J Am Geriatr Soc 33: 278-285, 1985

• 糖尿腎病變: GFR每年減少2-20 ml/min• 糖尿病若已合併大量白蛋白尿, 腎功能惡化速度平均高達11.2 ml/min per year

Scan J Clin Lab Invest 36: 381-388, 1976Diabetologia 20: 457-461, 1981Am J Med 74: 256-264, 1983

Tight BP control and ACEI slow down GFR decline rate by 3-4 ml/min/yr

GISEN group Lancet 349: 1857-1863, 1997Levey AS. JASN 10: 2426-2439, 1999

CV mortality in general population, dialysis, and kidney transplant

Foley RN. Am J Kidney Dis 32: S112-119, 1998

Prevalence of CVD in general population and CKD

Foley RN. Am J Kidney Dis 32: S112-119, 1998

Death or dialysis ?

Outline


Lipoprotein = lipid + protein

Apolipoprotein(apo)

TG, TC

Density and diameter of different lipoproteins

Lp class Density (g/ml) Diameter (nm)

HDL > 1.063 5-15

LDL 1.019-1.063 18-28

IDL 1.006-1.019 25-30

VLDL 0.95-1.006 30-80

Chylomicron < 0.95 100-1000

LDL and HDL subclasses by particle density and diameter

Krauss RM. Diabetes Care 27: 1496-1504, 2004

Size and density of Lipoproteins

chylomicron

HDL

Relative contents of lipoproteins(%)

Lp class TG TC Phospholipid Protein

Lp(a) 5 45 20 26

HDL 5 25 26 44

LDL 7 50 22 21

IDL 20 40 22 18

VLDL 60 20 14 6Chylomicron 90 5 3 2

Apolipoproteins subclasses

A A-I, II, IV, V

B B48, B100

C C-I, II, III, IV

D

E

H

Apo of different Lipoproteins

Lipoprotein class Apolipoprotein

Lp(a) Apo(a), B-100

HDL A-I, II, IV

LDL B-100

IDL B-100, E

VLDL B-100, C-II, III, E

Chylomicron B-48, C-II, III, A-IV, E

a lipoprotein particle

Major normal lipoprotein metabolic pathways

Fredrickson classification of hyperlipidemia

Outline

• Chronic kidney disease• Lipid metabolism and dyslipidemia• Renal dyslipidemia• Impacts of dyslipidemia on CV outcome• Impacts of dyslipidemia on renal outcome• Take home message

Lipid changes in various CKD stages

Lipid spectrum in renal disease

Pathogenesis of hypertriglyceridemia

• Downregulation of lipoprotein lipase, hepatic lipase, and the very low-density lipoprotein receptor

• Upregulation of hepatic acyl-CoAcholesterol acyltransferase

Pathophysiology of hypertriglyceridemia in uremia

LDL變形

• sdLDL• Oxidation • Carbamylation• Glycation

Outline


TC and relative risk of 6-yr CHD mortality for 356222 enrolled in MRFIT

Pekkanen J. N Engl J Med 322: 1700-1707, 1990

LDL reduction with statins and CVE reduction in 3 major trials

Hebert PR JAMA 278: 313-321, 1997

• With preexisting CHD, large-scale randomized trials have shown that lowering LDL by 40 mg/dL for 4 - 5 yr decreases the risk for coronary events and strokes by 25%

4S Trial. Lancet 344:1383-1389, 1994Heart Protection Study. Lancet 360:7-22, 2002Cheung BMY. Br J Clin Pharmacol 57:640-652, 2004

Event rates and LDL levels during secondary prevention studies

LaRosa JC. NEJM 352: 1425-1435, 2005

CAD risk reduction with LDL reduction > 55 mg/dl

After 1-2 yr After 3-5 yr After > 6 yr

33% 50% 52%

2006 ACC/AHA updates

• 2006 American College of Cardiology/ American Heart Association updates

• LDL ＜ 70 mg/dL as reasonable in all CHD patients, and those that could be characterized as very high risk

Smith SC Jr, Circulation. 2006;113:2363–2372

Baseline eGFR and future CV events

Go AS. N Engl J Med 351 : 1296 –1305, 2004

CV risk factors in CKD

Sarnak MJ. Am J Kidney Dis 35(suppl 1): S117-131, 2000

Tonelli M. Circulation 110: 1557-1563, 2004

Incidence of fatal CHD, nonfatal MI, and CAG in CKD + CHD


Incidence of all-cause mortality in CKD + CHD


Pravastatin Pooling Project

• GFR: 30 and 60 ml/min/1.73 m2 + known CHD => statins were good for CV outcome


TC and relative risk of death in HD

Lowrie EG. Am J Kidney Dis 15: 458-482, 1990

Causes of death in 4D study(Die Deutsche Diabetes Dialyse)

Wanner C. NEJM 353: 238-248, 2005

n= 1255 T2DM + MHDRandomly assigned to receive 20 mg/d atorvastatin or placebo

Causes of death in dialysis population

Ritz E. J Am Soc Nephrol 17: S226-230, 2006

Coronary arteries of a non-renal control patient (A) and a ESRD patient (B)Note thickening of the media and intima in renal disease

(A) Nonrenal (B) ESRD

SHARP studyeGFR(ml/min/1.73 m2) number Percentage(%)

≧60 88 0.93

30-59 2155 22.8

15-29 2565 27.1

＜15 1221 12.9

HD 2527 27

PD 496 5

Am Heart J 160: 785-794, 2010

SHARP study

• Full compliance would reduce risks of major atherosclerotic events by 25%

• Similar proportional reductions in all subgroups (including dialysis and non-dialysis)

Assessment of Lescol in Renal Transplant (ALERT) study

• Multicenter, randomized, double-blind, placebo-controlled trial

• n= 2102 renal transplant recipients• Compare fluvastatin with placebo• After a mean follow-up of 5.1 yr, fluvastatin

lowered LDL by 32%• Risk reduction with fluvastatin for primary CV

end point was not significant • No differences on renal allograft survival or renal

function

Holdaas H. Lancet 361: 2024-2031, 2003

ALERT extension study

• Mean follow-up 6.7 years• Mean LDL 98 mg/dL at last follow-up,

compared to a pre-study 159 mg/dL • Fluvastatin arm had a 29% reduction in

cardiac death or definite non-fatal MI

Holdaas H. Am J Transplant 5: 2929-2936, 2006

Outline


Agarwal R. Mayo Clin Proc 82(11):1381-1390, 2007

Helsinki Heart Study

• Finland—the Helsinki Heart Study• White men, non-HDL > 200 mg/dl + Cr

4.4 had a 20% faster

decline than ratio of < 0.2

Manttari M. Hypertension 26: 670–675, 1995

Effect of LDL/HDL ratio on GFR decline

Manttari M. Hypertension 26: 670–675, 1995

Physicians Health Study

• 4483 healthy male physicians were followed between 1982 and 1996

• Primary end points: (1) Cr >1.5 mg/dl (2) eGFR

Association between initial TC and future Cr > 1.5 mg/dl

Schaeffner ES. J Am Soc Nephrol 14 : 2084 –2091, 2003

Atherosclerosis Risk in Communities Study

• Men with serum Cr ＜2.0 mg/dL, and women with Cr＜ 1.8 mg/dL were followed

• Higher HDL were associated with a decreased risk of progression, defined as an increase in Cr ＞ 0.4 mg/dL

• In terms of non–HDL, only high TG were associated with increased risk of CKD progression

Muntner P. Kidney Int. 2000;58:293–301

Relationship between GFR decline rate and apoB-containing Lp levels

Attman PO. Kidney Int 56:S14-17, 1999

(TC-rich)

(TG-rich)

Pravastatin vs placebo slower down GFR decline rate by:

Baseline GFR, ml/min/yr Reduction, ml/min/yr

60-89.9 0.06

40-59.9 0.22

30-39.9 0.71


Meta-analysis:statins slow down GFR decline rate by 1.2 ml/min/yr

J Am Soc Nephrol 17: 2006-2016, 2006

SHARP study

• No substantial effect on CKD progression

One way ticket ?

DyslipidemiaCKD

Agarwal R. Mayo Clin Proc 82(11):1381-1390, 2007

K/DOQI

Take home message

• Renal dyslipidemia is different from that of general population

• Earlier treatment of renal dyslipidemia is good for CV protection

• Treatment of renal dyslipidemia might be good for renal protection

血脂異常與慢性腎病OutlineOutlineCKD staging and prevalenceEquations to calculate GFRCV mortality in general population, dialysis, and kidney transplantPrevalence of CVD in general population and CKDOutlineLipoprotein = lipid + proteinDensity and diameter of different lipoproteinsLDL and HDL subclasses by particle density and diameterSize and density of LipoproteinsRelative contents of lipoproteins(%)Apolipoproteins subclassesApo of different Lipoproteinsa lipoprotein particleMajor normal lipoprotein metabolic pathwaysFredrickson classification of hyperlipidemiaOutlineLipid changes in various CKD stagesLipid spectrum in renal diseasePathogenesis of hypertriglyceridemiaLDL變形OutlineTC and relative risk of 6-yr CHD mortality for 356222 enrolled in MRFITLDL reduction with statins and CVE reduction in 3 major trialsEvent rates and LDL levels during secondary prevention studiesCAD risk reduction with LDL reduction > 55 mg/dl2006 ACC/AHA updatesBaseline eGFR and future CV eventsCV risk factors in CKD

Documents

Dyslipidemia and CKD - sltung.com.t · 2017-03-20 · Assessment of Lescol in Renal Transplant (ALERT) study • Multicenter, randomized, double-blind, placebo-controlled trial •