Traditional risk factors—such as diabetes, hypertension, dyslipidemia—and those specific to dialysis patients (anemia and mineral metabolism abnormalities) require regular assessment and treatment as per current recommendations. The relative importance and weight of each of these risk factors in the dialysis population is not known and, in the absence of controlled trials in this population, current recommendations from existing organizations should be followed, with special consideration given to potential risks.
Furthermore, lifestyle issues such as smoking, physical activity, depression, and anxiety are the cornerstones of therapy as in the general population. The treatment options are often similar, but the impact of these factors is potentially more profound in dialysis patients. These factors are all discussed in this section. Special attention will be paid to the difference between the usual recommendations and those for dialysis patients.
Guideline 13: Dyslipidemia
Since the NKF KDOQI Clinical Practice Guidelines for Managing Dyslipidemia in Chronic Kidney Disease Patients were established only recently,51 we refer to those guidelines. However, we add the information on four recent studies that provide some new insights on the inverse association between cholesterol level and mortality, as well as further indirect evidence of the beneficial effects of lipid-lowering therapy. Furthermore, unpublished results of the recently completed “4D Trial” on the effect of statins in chronic HD patients recently became available and will be discussed.
Management of dyslipidemias for prepubertal children with CKD and CKD Stage 5 should follow recommendations by National Cholesterol Expert Panel in Children and Adolescents. Postpubertal children or adolescents with CKD Stages 4 and 5 should follow the recommendations provided in the KDOQI Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease.51
Association between dyslipidemia and CVD in dialysis patients (Weak)
The previous guidelines listed the studies, which investigated an association between cholesterol levels and CVD, and discussed the often-observed “paradoxical association” between dyslipidemia and CVD in HD patients, i.e., that higher cholesterol levels are apparently associated with better outcomes in HD patients. As one of several explanations it was mentioned that none of the previous studies was a long-term, prospective cohort study and that illness, inflammation, and poor nutrition might have confounded the relationship between dyslipidemia and CVD. This was recently observed in a study investigating the association of cholesterol levels with all-cause and CVD mortality in a prospectively followed cohort of 823 patients who initiated dialysis treatment.262 During a median follow-up of 2.4 years, 324 deaths (including 159 CVD deaths) occurred. Average serum cholesterol level was lower in the presence of inflammation/malnutrition than in its absence. A higher baseline total serum cholesterol level was associated with a decreased risk of all-cause mortality overall and in the presence of inflammation/malnutrition. In contrast, a higher serum cholesterol level was associated with an increased risk in the absence of inflammation/malnutrition. For CVD mortality, an inverse trend was not statistically significant in the presence of inflammation/malnutrition, and a positive association was evident in the absence of inflammation/malnutrition. The authors concluded that the inverse association of total cholesterol level with mortality in dialysis patients is likely due to the cholesterol-lowering effect of systemic inflammation and malnutrition, not to a protective effect of high cholesterol concentrations. These findings would support the treatment of hypercholesterolemia in dialysis patients.
Indirect evidence for lipid-lowering therapy in kidney disease (Weak)
Even if the present guidelines focus on dialysis patients, further indirect evidence for the beneficial effect of lipid-lowering intervention comes from three additional studies. A multicenter, randomized, double-blind, placebo-controlled trial of 40–80 mg fluvastatin was conducted in 2,102 kidney transplant recipients followed for 5–6 years.263 Fluvastatin reduced LDL cholesterol concentrations by 32%. Risk reduction for the composite primary endpoint including myocardial infarction, cardiac death and cardiac interventions did not reach significance although the fluvastastin group experienced a third fewer cardiac death and nonfatal MI than the placebo group. Coronary intervention procedures and other secondary endpoints were not significantly different between the two groups.
Another study was performed in more than 19,000 hypertensive patients with at least three other CVD risk factors.264 Patients with non-fasting cholesterol concentrations of 6.5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. A prespecified subgroup analysis in 6517 patients with kidney dysfunction revealed a significantly lower risk for the primary endpoint (nonfatal MI or cardiac death) in the atorvastatin group when compared to placebo.
A randomized trial of pravastatin versus placebo in 4,159 patients with previous MI and total plasma cholesterol level <6.21 mmol/L performed a post hoc analysis in 1,711 patients with CKD.265 After a median follow-up of almost 5 years, the incidence of the primary end point (coronary death or nonfatal MI) was lower in patients receiving pravastatin than in those receiving placebo, suggesting that pravastatin is effective for secondary prevention of cardiovascular events in persons with mild chronic kidney insufficiency.
4D Trial
Together with the Heart Protection Study,266 all four studies support the hypothesis that lipid-lowering intervention might be beneficial in patients with kidney insufficiency.
The latest results came from the “4D Trial” (Deutsche Diabetes Dialyse Studie) which have not yet been published. It was a randomized, placebo-controlled study in 1,255 type 2 diabetic patients on chronic HD.267 Out of those patients, 619 were treated with 20 mg atorvastatin compared to 636 matched controls treated with placebo for a median of 4 years. The statin was safe and effective in reducing the median serum LDL cholesterol level by 42% throughout the study period. However, the primary endpoint—defined as the composite of cardiac death, nonfatal MI, and fatal or nonfatal stroke—was only reduced by 8% which was not statistically significant (Christoph Wanner for the 4D Study investigators, American Society Nephrology 37th Annual Meeting, October 2004). This was in distinct contrast to the recently published CARDS trial (Collaborative Atorvastatin Diabetes Study) in type 2 diabetic patients who had not yet developed significant kidney disease.268 In that study, atorvastatin reduced the rate of acute coronary events by 36%, coronary revascularization by 31%, stroke by 48%, and death by 27%. The 4D investigators concluded that the negative results might have been due to the advanced cardiovascular diseases in the chronic HD patients, and because statin therapy was initiated too late. Therapy might better be started during the early stages of disease progression as demonstrated by the CARDS study. There are, of course, other potential explanations for these results, which would warrant further studies. Whether the effect of statin reported in the 4D Trial on diabetic dialysis patients is different in nondiabetic dialysis patients or chronic PD patients needs to be further investigated.
Recent NCEP report on ATP III guidelines
A recent report from the National Cholesterol Education Program (NCEP) discussed the implications of clinical trials on the Adult Treatment Panel III (ATP III) guidelines.269 Results from the Heart Protection Study and the PROVE IT Study suggested that additional benefit may be obtained by reducing LDL cholesterol levels to substantially below 100 mg/dL. Since other studies are underway to prove the efficacy of lowering LDL to very low levels, the NCEP report stated that “until these trials are completed, prudence requires that setting an LDL-C goal of <70 mg/dL for high-risk patients must be left as a therapeutic option on the basis of clinical trial evidence, whereas a goal of <100 mg/dL can be retained as a strong recommendation. Factors that favor a decision to reduce LDL-C levels to <70 mg/dL are those that place patients in the category of very high risk.”