Although cardiovascular disease accounts for the largest proportion of deaths in both the chronic kidney disease (CKD) and the dialysis populations, interventions to prevent these have been limited. In the dialysis population, statin trials were clearly negative, and the effect of a statin-ezetimibe combination, even in CKD patients, was not as impressive as in the general population.
Many reasons have been offered to explain this seeming paradox: the role of non-traditional risk factors (eg inflammation, vascular calcification), greater mortality from heart failure and arrhythmias rather than acute plaque rupture, and a distinct atherosclerotic process in CKD/dialysis patients with more arteriosclerosis and small vessel disease. In addition, the reverse epidemiology phenomenon, with lower cholesterol being associated with higher mortality, may reflect the malnutrition-inflammation state. In a recent review published in AJKD of cholesterol metabolism in CKD, Reiss and colleagues show the disruption of normal cholesterol physiology in CKD that can underlie and explain these outcomes.
CKD is associated with increased plasma triglyceride and VLDL-cholesterol levels, and decreased HDL-cholesterol levels. However, total and LDL-cholesterol may be normal, or even decreased, and despite this, CKD patients are at higher risk for CV events. Going beyond just the serum levels of these circulating molecules to their effects on vascular endothelium provides a greater insight into why this may be. Though LDL-cholesterol has been labelled as the “bad” cholesterol, it actually encompasses particles of various sizes and properties. Small-dense LDL can breach the endothelial monolayer and is the most pro-atherogenic. Lipoprotein a (LPa) is a modified LDL which is markedly pro-atherothrombotic, and is normally degraded in the kidney. The increase in triglycerides reflects a higher presence of chylomicron remnants, which can also penetrate vascular endothelium and induce atherosclerosis.
Similarly, there is a change in the HDL (aka “good”) cholesterol subtypes, with less of the cardio-protective HDL-2 and more of the lipid-poor HDL-3. The reverse cholesterol transport mediated by HDL cholesterol is impaired by decreased expression of key cholesterol transporters (ABCA1 and ABCG1), impaired synthesis of apolipoprotein A1, and decreased LCAT activity. The changes in HDL cholesterol function are particularly interesting (see Figures 2 and 3 from the Reiss review) showing how HDL cholesterol not only becomes less protective, but pro-inflammatory with promotion of endothelial dysfunction. Lastly, the picture is complicated by the role of uremic toxins, such as malondialdehyde, indoxyl sulfate, and urea (carbamylated LDL is pro-atherogenic).
Does this information help us in lowering the risk of cardiovascular disease in CKD? It does help explain why statins may not necessarily be that effective, though the pleiotropic effects should still apply. The details regarding derangements at the molecular and enzymatic level does identify many potential targets for inhibitors and antibodies in this era of precision medicine.
Dr. Swapnil Hiremath
AJKD Blog Contributor