1. Dyslipidemia in Chronic Kidney Disease
Mini topic
Dyslipidemia in Chronic Kidney Disease
신장내과
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2. Introduction
Cardiovascular disease: Major cause of mortality in patients with mild to moderate CKD and ESRD
Approximately 50% of patients with ESRD die from a cardiovascular event
Cardiovascular mortality > 30 times in Dialysis patients, 500 times higher in 25~34 year old ESRD
Dyslipidemia
Well-known traditional risk factor for CVD in the general population
CKD exhibit Significant alterations in lipoprotein metabolism
Am J Nephrol 2008;28:958–973

3. Lipoprotein metabolism pathway
Exogenous
Endogenous
Exogenous pathway: Fatty acid in small intestine  TG  Packaged and Secreted as Chylomicron  FFA + Chylomicron remnants
Endogenous pathway: VLDL FFA + IDL  LDL
Am J Nephrol 2008;28:958–973

4. Effects of renal failure on serum lipids
TG↑: Early feature of renal failure
Downregulation of the expression of several genes, Changes in the composition of lipoprotein particles, Uremic toxins, Impaired insulin sensitivity
HDL-C↓: Impaired reverse cholesterol transport
Accumulation of TG-rich lipoproteins(VLDL, Chylomicrons): Mainly due to their decreased catabolism
다양한 유전자의 Down regulation, Lipoprotein particle 의 조성의 변화, Uremic toxin의 direct inhibition 작용, CKD 환자에서 Insulin sensitivity에 장애가 생기는데 Insulin resistance 증가로 따른 VLDL의 overproduction이 TG 증가를 유발합니다.
Am J Nephrol 2008;28:958–973

5. Assessment of lipid status in adults with CKD
Newly identified CKD: Evaluation with a lipid profile (Total cholesterol, LDL-C, HDL-C, TG)
TG> 11.3mmol/l(1000mg/dl) or LDL-C > 4.9mmol/l(190mg/dl)  Prompt consideration of further evaluation
LDL-C
Previous guidelines: Indication for pharmacological treatment with lipid-lowering agents, targets by increasing the dose of statin
Now: Higher cardiovascular risk and not elevated LDL-C is the primary indication to initiate lipid-lowering treatment in CKD patients
Follow-up measurement of lipid levels is not required for the majority of patients.
KDIGO Clinical Practice Guideline(2013)

6. Pharmacological cholesterol lowering treatment
LDL-C is not suitable for identifying CKD patients who should receive pharmacological cholesterol-lowering treatment
Associations between LDL-C and coronary artery disease in CKD patients with eGFR >15ml/min/1.73 m2
The weaker and potentially misleading association between LDL-C and coronary risk among those with lower levels of kidney function (a group who is at the highest absolute risk) argue against its use for identifying CKD patients who should receive pharmacological cholesterol lowering treatment

7. Pharmacological cholesterol lowering treatment
Which CKD patients should receive pharmacological cholesterol-lowering treatment?
The rate of coronary death or incident MI among patients with CKD (defined by eGFR 15–59.9ml/min/1.73m2
or with heavy proteinuria) is similar to or higher than those with diabetes (with or without CKD). However, the risk
associated with CKD is age-dependent. For example, the rate of coronary death or incident MI among CKD patients
aged 450 years (both men and women) is consistently greater than 10 per 1000 patient-years, even in those without
diabetes or prior MI) (Figure 2; Table 3). In contrast, the rate of coronary death or incident MI among CKD patients aged
r50 years is low in those without diabetes or prior MI

8. Pharmacological cholesterol lowering treatment
How should the dose of pharmacological cholesterol-lowering treatment be determined in CKD patients?
High risk of medication-related adverse events, perhaps because of the reduced renal excretion, frequent polypharmacy and high prevalence of comorbidity in this population
CIx: Pregnant , Breast-feeding, Active liver disease, Transaminase levels that are three times or more the upper limit of normal

9. Pharmacological cholesterol lowering treatment
Age >50 years with eGFR < 60 but not treated with chronic dialysis or kidney transplantation (GFR G3a-G5)  Statin or Statin/ ezetimibe combination. (1A)
Age >50 years with CKD and eGFR >60(GFR G1-G2)  Statin. (1B)
Age years with CKD but not treated with chronic dialysis or kidney transplantation, One or more of the following  Statin (2A)
Known coronary disease (myocardial infarction or coronary revascularization)
Diabetes mellitus
Prior ischemic stroke
Estimated 10-year incidence of coronary death or non-fatal myocardial infarction >10%
The SHARP trial: Statin plus ezetimibe therapy led to a significant 17% reduction in the relative hazard of the primary outcome of major atherosclerotic events (coronary death, MI, non-hemorrhagic stroke, or any revascularization) compared with placebo (HR 0.83; 95% CI
0.74–0.94)
KDIGO Clinical Practice Guideline(2013)

10. Pharmacological cholesterol lowering treatment
In adults with dialysis-dependent CKD, we suggest that statins or statin/ezetimibe combination not be initiated. (2A)
The 4D Study (Die Deutsche Diabetes Dialyse Studie)
AURORA Study (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Dialysis: an Assessment of Survival and Cardiovascular Events)
SHARP (Study of Heart and Renal Protection)
In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest that these agents be continued. (2C)
In adult kidney transplant recipients, we suggest treatment with a statin. (2B)
KDIGO Clinical Practice Guideline(2013)

11. Triglyceride-lowering treatment
In adults with CKD (including those treated with chronic dialysis or kidney transplantation) and hypertriglyceridemia, we suggest that therapeutic lifestyle changes be advised. (2D)
Fibric acid derivatives: TG> 1000 mg/dl(Weak recommendation)
Cardiovascular risk: Not recommended
Pancreatitis: Extremely weak evidence
Nicotinic acid: Not well studied in advanced CKD, Risk of toxicity (Especially flushing and hyperglycemia)
KDIGO Clinical Practice Guideline(2013)

12. Dyslipidemia in Kidney transplantation recipient
Dyslipidemia in KT recipient: LDL-C↑, TG ↑, HDL-C↓
Approximately 90% of patients with cyclosporine and steroid-based immunosuppression have LDL-C> 100 mg/dl
LDL-C
Associated with cardiovascular disease and mortality in the general population and in renal transplant recipients TG
Treating ≥500 mg/dl to reduce the risk of pancreatitis
Transplantation Reviews (2014)

13. Dyslipidemia in Kidney transplantation recipient
Measure a complete lipid profile in all adult (≥18 years old) and adolescent (puberty to 18 years old) KTRs
2–3 months after transplantation
2–3 months after a change in treatment or other conditions known to cause dyslipidemias;
At least annually, thereafter
KTRs with fasting TG ≥500 mg/dL that cannot be corrected by removing an underlying cause
Adults: therapeutic lifestyle changes and a triglyceride lowering agent
Adolescents: therapeutic lifestyle changes
KDIGO Clinical Practice Guideline(2009)

14. Dyslipidemia in Kidney transplantation recipient
KTRs with elevated LDL-C
Adults: If LDL-C ≥100 mg/dL, treat to reduce LDL-C to <100 mg/dL
Adolescents: If LDL-C ≥130mg/dL (≥3.36 mmol/L), treat to reduce LDL-C to <130 mg/dL
For KTRs with normal LDL-C, elevated triglycerides and elevated non-HDL-C
Adults: If LDL-C <100 mg/dL, fasting triglycerides ≥200 mg/dL, and non-HDL-C ≥130 mg/dL, treat to reduce non-HDL-C to <130 mg/dL
Adolescents: If LDL-C <130mg/dL, fasting triglycerides ≥200 mg/dL, and non-HDL-C ≥160 mg/dL, treat to reduce non-HDL-C to <160 mg/dL
KDIGO Clinical Practice Guideline(2009)

15. Hypercholesterolemia in Kidney transplantation recipient
Statin: The most efficient intervention to reduce cardiovascular events and cardiac death
Reduction of 32% in myocardial infarction and 38% in the risk of cardiac death
Bioavailability of statins in renal transplant patients
Bioavailability ↑ due to the inhibition of hepatic and intestinal P-glycoprotein by cyclosporine
Simvastatin, Atorvastatin: 6 ~ 15 fold increases in AUC in combination with cyclosporine
Fluvastatin: Pharmacokinetic profile is not altered by cyclosporine treatment
Exposure to tacrolimus had no such effect and did not interfere with statin pharmacodynamics
Transplantation Reviews (2014)

16. Hypertriglyceridemia in Kidney transplantation recipient
General population: Statin and fibric acid or nicotinic acid
LDL-C↓, TG ↓, HDL-C↑
Drawback of Statin + Fibrates in KT recipient
Detrimental effect on graft function
Mistaken for acute rejection
Reversible functional effect and not due to renal damage in the large FIELD and ACCORD trials
Gemfibrozil: the only fibrate that has not been linked with a reduction in renal function
Drug interaction: Glucuronidaton  Statin concentration ↑
Rhabdomyolysis
concomitant increase in urea [157], cystatin
C and homocysteine [159,160]. The effect of fibrates on renal
function appears to be mediated by a reversible functional effect
linked to downregulation of the inducible COX-2 enzyme and a
decreased synthesis of vasodilatory prostaglandins as a consequence
of binding and activation of the peroxisome proliferator-activated
receptors
Transplantation Reviews (2014)

17. Hypertriglyceridemia in Kidney transplantation recipient
Atorvastatin + Ezetimibe
Interesting alternative to fibrates
Reduction of TG by 30 ~ 40% in a large controlled trial and in a retrospective cohort of 34 KT patients
Statin + Nicotinic acid
TG ↓, HDL-C↑, but Not reduce CVD outcomes as compared to Statins alone
Myopathy
Combination therapy was associated with a four-fold increase

18. Reference
KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease(2013)
Dyslipidemia in Chronic Kidney Disease: An Approach to Pathogenesis and Treatment(Am J Nephrol 2008;28:958–973)
KDIGO Clinical practice guideline for the care of kidney transplant recipients(2009)
Obesity, metabolic syndrome and diabetes mellitus after renal transplantation: Prevention and treatment(Transplantation Reviews 28 (2014) 37–46)