1. What is the typical lipid profile in patients with chronic kidney disease (CKD)?

Dyslipidemias are common in patients with CKD, those on dialysis (both hemodialysis and peritoneal dialysis), and those who have undergone kidney transplantation. Dyslipidemia is also prevalent in over 60% of people who have received cardiac or liver transplantation, and this may be partially due to the long-term use of calcineurin inhibitors and/or steroids as immunosuppressants. Proteinuria, and particularly nephrotic syndrome, is associated with a greater elevation in total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein(a) (Lp-a) than in persons with CKD without proteinuria. The concentration of high-density lipoprotein (HDL) cholesterol is also often reduced in nephrotic syndrome. Hemodialysis and peritoneal dialysis patients have increased levels of triglycerides and Lp-a compared to patients with milder degrees of CKD, with peritoneal dialysis patients having particularly atherogenic lipid profiles, perhaps due to constant dextrose absorption. LDL cholesterol is often normal or low in hemodialysis patients, perhaps due to poor nutrition and chronic inflammation. Table 22.1 depicts the most common lipid abnormalities seen across the spectrum of kidney disease.

2. What are the unique characteristics of the pathophysiology of dyslipidemia in CKD?

A number of unique clinical features among patients with CKD and those on dialysis lead to changes in the structure and function of lipid molecules. Uremia and frequent heparinization in dialysis patients can decrease the activity of lipoprotein lipase and hepatic triglyceride lipase necessary to cleave triglycerides into free fatty acids. Incomplete triglyceride catabolism causes an accumulation of remnant particles (chylomicrons) that contribute to increased atherosclerosis. Although the concentration of LDL cholesterol is often no higher than that in the general population, there are differences in the qualitative nature of LDL cholesterol. Small dense LDL (sdLDL) and intermediate LDL (ILDL) fractions are increased in CKD. The decreased activity of lipases described above prevents the degradation of very-low-density LDL (VLDL) into LDL cholesterol, resulting in the accumulation of ILDL. The increased plasma residence time of these particles further results in structural changes in the apo(B) protein they carry, decreasing hepatic clearance. Decreased clearance by the liver results in uptake by macrophages, which may result in adherence to the vascular endothelium, leading to plaque formation.

CKD is also associated with change in the distribution of HDL cholesterol fractions. Low apo-AI level and decreased lecithin:cholesterol acyltransferase (LCAT) activity result in reduced esterification of free cholesterol and a reduced cholesterol-carrying capacity of HDL molecules. Proteinuric kidney diseases, especially nephrotic syndrome, are characterized by elevations in plasma Lp(a) concentrations, LDL, and total cholesterol due to increased liver production. In addition, there is a reduction in the cardioprotective HDL2 component of HDL cholesterol. Proteinuria also leads to an elevated free fatty acid to albumin ratio. Angiopoietin-like 4 (angptl4) is a protein expressed primarily in the liver, and its levels are elevated in nephrotic syndrome in response to these free fatty acids. Angptl4 inhibits lipoprotein lipase, leading to hypertriglyceridemia in persons with nephrotic syndrome.

3. When should patients with kidney disease be evaluated for dyslipidemia?

Recent guidelines from the Kidney Disease Improving Global Outcomes (KDIGO) have recommended that all adult patients with newly identified CKD, including those on dialysis or kidney transplant recipients, should be evaluated with a lipid profile. Although the evidence to suggest improved clinical outcomes after measuring lipids is lacking, the risks of testing are low, and the data may provide information on cardiovascular disease (CVD) prognosis and guide treatment.

4. What tests should be used to evaluate dyslipidemia in patients with CKD?

As with the general population, a complete lipid profile including total, HDL, LDL cholesterol, and triglycerides should be obtained when evaluating dyslipidemia. While a lipid profile obtained after an overnight fast is ideal, even nonfasting values can provide important information. Fasting lipid profiles should be considered when significant abnormalities, especially high triglycerides, are noted with non-fasting samples. The routine measurement of lipoprotein(a), apolipoprotein B, and other lipid markers is not recommended due their lack of utility in current clinical practice.

5. How often should lipids be checked in persons with CKD and dyslipidemia?

There is no recognized clinical benefit of measuring lipids annually in most people with CKD, especially if they are already on a statin. Possible reasons for remeasuring lipids include:

• 1.
  

  Assessing treatment adherence by ensuring an appropriate decrease in LDL cholesterol levels, although this can be achieved through questionnaires, pill counts, and verifying prescription refills.

  
  
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  Reevaluating the 10-year CVD risk in persons younger than 50 years of age who are not being treated with a statin.

  
  
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  Determining the need for a greater treatment intensity to achieve target lipid goals (at least 30% reduction in LDL cholesterol) after initial treatment is begun.

6. Are the principles of testing different in children with CKD?

A number of organizations, including the American Academy of Pediatrics, American Heart Association, and KDIGO, recommend that all children older than 2 years of age with any CVD risk factors, including CKD, have a fasting lipid profile checked. In contrast to adults, despite an absence of high-quality evidence, it is recommended that children undergo annual fasting lipid profiles in order to detect secondary causes of dyslipidemia, and because growth and development can affect the lipid profile.

7. What is the association of dyslipidemia with CVD and mortality in patients with CKD?

Unlike in the general population, the linear association between higher levels of cholesterol and CVD-related mortality is less evident in patients with CKD, especially those on dialysis. Instead, observational studies have demonstrated a “reverse epidemiology” between total cholesterol levels and mortality in dialysis patients; that is, increased risk at low cholesterol levels, with evidence that malnutrition and chronic inflammation may act as affect modifiers of this association. Hypercholesterolemia is an independent risk factor for cardiovascular and all-cause mortality in dialysis patients without evidence of malnutrition or inflammation. Observational data from non-dialysis CKD populations has been conflicting. Data from the Atherosclerosis Risk in Communities (ARIC) study suggested that higher total cholesterol and triglyceride levels were associated with a higher risk of CVD events in patients with CKD. However, the Cardiovascular Health Study (CHS) and the Modification of Diet in Renal Disease (MDRD) study reported that dyslipidemia was not associated with the increased risk of kidney failure and cause, or CVD mortality.

8. Does treatment of dyslipidemia reduce the risk of CVD events and mortality in patients with CKD?

The 10-year cardiovascular risk for most adults over the age of 50 years with CKD is >10%, thereby meeting the general population requirements for statin therapy. Data supporting the use of statins in the primary prevention of CVD comes primarily from post hoc analysis of trials of the general population. A meta-analysis of 50 such trials, which included 45,285 participants with stage 3 or 4 CKD, reported a significant reduction in all-cause and cardiovascular mortality and nonfatal CVD outcomes. The best randomized controlled trial (RCT) evidence in patients with CKD comes from the Study of Heart and Renal Protection (SHARP) trial, which is the only randomized trial to focus on statin therapy for the primary prevention of CVD events and mortality in patients with kidney disease. The SHARP trial included 9438 participants with CKD with a mean estimated glomerular filtration rate (eGFR) of 27 mL/min per 1.73 m². Participants were randomized to either simvastatin 20 mg, ezetimibe 10 mg, or placebo. Among 6247 SHARP participants with CKD not on dialysis, there was a reduced incidence of CVD mortality, nonfatal myocardial infarction, and stroke (9.5% vs. 11.9%) among patients treated with simvastatin and ezetimibe compared to placebo. Whether combination therapy with ezetimibe is superior to monotherapy with statins in CKD patients is yet unknown.