Association of Sphingolipids with All-Cause and Cardiovascular Death in Patients with Kidney Failure Treated with...

Sphingolipids with long fatty acids (16-18 carbons) were associated with all-cause and cardiovascular death in patients treated with hemodialysis. Sphingolipids with very-long fatty acids (20+ carbons) were associated with lower risk of all-cause and cardiovascular death in dialysis patients.

Patients with kidney failure on hemodialysis are at a higher risk for death, especially cardiovascular death. Statins (which improve outcomes in general populations) do not improve outcomes in dialysis patients. Sphingolipids are mechanistically associated with cardiovascular disease and may represent novel, modifiable risk factors for death in patients with kidney failure. We aimed to examine the associations of sphingolipids with death specifically in dialysis patients.

Using data from the Hemodialysis (HEMO) Study (a multicenter factorial trial of dose and flux), we measured 16 sphingolipids (ceramides-16:0, 18:0, 20:0, 22:0, 24:0, and 24:1; hexosylceramides-16:0, 22:0, and 24:0; lactosylceramide-16:0; and sphingomyelins 14:0, 16:0, 18:0, 20:0, 22:0, and 24:0) at baseline only in 927 participants with available stored serum using targeted liquid chromatography-tandem mass spectrometry. The primary outcome was all-cause death, with physician-adjudicated cause (cardiovascular versus noncardiovascular) as a secondary outcome. We examined the associations of sphingolipids with death using Cox regressions, controlling the false discovery rate <5%.

Among 927 participants, the mean (SD) age was 57 (14) years; median (interquartile range) dialysis vintage was 1.9 (0.8-4.1) years. Over a median (interquartile range) follow-up of 2.4 (1.4-4.0) years, there were 376 deaths. Nine of 16 sphingolipids were significantly associated with death, including ceramide-16:0 (adjusted hazard ratio [aHR] 2.13 per two-fold higher concentration, 95% confidence interval, 1.48 to 3.06), and ceramide-22:0 (aHR per two-fold higher 0.59, 95% confidence interval, 0.44 to 0.79), with similar direction of associations for sphingomyelins. Twelve of 16 sphingolipids were associated with cardiovascular death, for example, ceramide-16:0 (aHR per two-fold higher 3.43, 95% confidence interval, 2.05 to 5.74). No sphingolipid was significantly associated with noncardiovascular death.

In a dedicated study of patients with kidney failure on hemodialysis, sphingolipids with long-chain fatty acids were strongly associated with greater risk of death, especially cardiovascular death.