Lipid Metabolism and Cardiovascular Morbidity and Mortality in Hemodialysis Patients: Role of Factors Modulating Cytosolic Calcium

Animal studies indicate that insulin resistance and glucose intolerance leading to dyslipidemia in uremic rats are associated with increased cytosolic calcium ([Ca⁺⁺ i]). The resistance and intolerance are reversed with verapamil, but recur after its discontinuation. This finding suggests that hyperparathyroid‐induced [Ca ⁺⁺ i] increase is responsible for the metabolic derangement. We retrospectively examined, over a 12‐year period, the effects of factors that lower [Ca ⁺⁺i] on total serum cholesterol and triglycerides in 332 hemodialysis (HD) patients. Because the study was retrospective, detailed lipid profiles were not available. We therefore relied on morbidity and mortality outcomes related to atherosclerotic vascular disease. Patients with diabetes mellitus were excluded, because their dyslipidemia and vascular disease are mediated via a different mechanism. Four groups emerged: group I [high parathormone (PTH) in the absence of calcium channel blockers (CCBs), n = 107], representing the highest [Ca⁺⁺ i]; group II (high PTH in the presence of CCBs, n = 76) and group III (lower PTH in the absence of CCBs, n = 66), representing intermediate [Ca ⁺⁺ i]; and group IV (lower PTH in the presence of CCBs, n = 83) representing the lowest [Ca ⁺⁺i]. The theoretically lower [Ca ⁺⁺ i] was achieved via CCB therapy or lower PTH, or both. The mean serum cholesterol in group I was 322 ± 24 mg/dL and the level of triglycerides was 398 ± 34 mg/dL. Group II had mean serum cholesterol of 196 ± 16 mg/dL and triglycerides of 157 ± 17 mg/dL. Group III had a mean serum cholesterol of 202 ± 19 mg/dL and triglycerides of 160 ± 15 mg/dL. Group IV had a mean serum cholesterol of 183 ± 9 mg/dL and triglycerides of 94 ± 6 mg/dL. The differences in cholesterol and triglyceride levels among four groups were significant (p < 0.001) by one‐way analysis of variance (ANOVA). The incidence of cardiovascular morbidity and mortality events was 61% in group I, 24% in group II, 28% in group III, and 18% in group IV (χ ² = 47.7, p < 0.001). We conclude that, in non diabetic HD patients, hyperparathyroidism, especially in the absence of CCBs, is associated with severe dyslipidemia and increased risk of cardiovascular morbidity and mortality. Dyslipidemia may be related to a hyperparathyroid‐induced increase in cytosolic calcium [Ca⁺⁺i]. Lowering [Ca⁺⁺i] by decreasing PTH or by blocking calcium entry into cells (via CCBs), or both, is associated with less dyslipidemia and improved long‐term cardiovascular morbidity and mortality. Prospective randomized studies, with actual measurement of [Ca ⁺⁺i], are needed to verify the results of this study.