Low cholesterol in dialysis patients-causal factor for mortality or an effect of confounding?

Background. The association between cholesterol and mortality is reversed in end-stage renal disease (ESRD). This phenomenon has many potential explanations, one of them being 'time discrepancy of competing risks'. It states that hypercholesterolaemia is beneficial only in the short term, while it worsens survival over a long-term interval. It is also proposed that the reversed relationship between cholesterol and outcome is due to confounding protein-energy wasting. The aim of the study was to verify the hypothesis of time discrepancy of competing risks in 1191 incident dialysis patients (Netherlands Cooperative Study on the Adequacy of Dialysis). Methods. Conditional Cox proportional hazards analysis was applied, where associations between cholesterol level and short-term versus long-term mortality were being compared. Furthermore, to evaluate associations between cholesterol and outcome free from confounding, Mendelian randomization was introduced, using apolipoprotein E (apoE) genotype. Results. Hypercholesterolaemia (>240 mg/dL) was associated with improved 5-year survival when compared to the low cholesterol group (<200 mg/dL), hazard ratio (HR) 0.62 (0.47-0.82), P < 0.001. However, conditional Cox proportional hazards analysis revealed that the reverse association between high cholesterol and all-cause mortality was evident only during the first year of follow-up, HR = 0.43 (0.23-0.80), P < 0.01, and then, gradually, declined. The apoE genotype significantly affected cholesterol concentration. The epsilon 2 carriers, associated with low cholesterol, had significantly increased risk of non-cardiovascular mortality. Conclusions. Reverse association between cholesterol concentration and mortality in dialysis patients is short-termed, consistent with the hypothesis of time discrepancy of competing risks. Low cholesterol appeared to affect non-cardiovascular mortality in ESRD patients free from confounders.