Work

Ceramides Are Elevated in Transplant-Associated Thrombotic Microangiopathy in Hematopoietic Stem Cell Transplant Recipients and Are a Druggable Target for Prophylaxis.

Year: 2024

Type: article

Abstract: Ceramides (Cer) are sphingolipids critical to maintaining endothelial barrier homeostasis and integrity. Ceramides cause oxidative stress in human endothelial cells, thereby reducing levels of bioactive nitric oxide (NO). NO inhibits platelet aggregation, prevents adhesion of platelets to the endothelial surface and induces disaggregation of aggregating platelets. We hypothesized that disruption of ceramides contributes to the etiology of TA-TMA and that ceramides represent a target for prophylaxis. We studied 135 consecutive pediatric and young adult allogeneic-HSCT patients at baseline (prior to start of transplant) and on day 14 from stem cell infusion. Plasma samples were analyzed using mass spectrometry to determine concentrations of ceramide species of varying acyl chain lengths. We specifically evaluated whether plasma concentrations in patients with TA-TMA differed when compared to patients without TA-TMA. Patient demographics and transplant-related characteristics are described in Figure 1. Forty-three (31.9%) patients were diagnosed with TA-TMA a median of 31 days (range 7-378 days) from HSCT. We observed significantly increased concentrations of long-chain (C14:0-C20:0) and very long-chain (C22:0-C26:0) ceramide species at baseline in patients diagnosed with TA-TMA compared to patients without TA-TMA. Baseline concentrations of C16 were higher in patients with TA-TMA (246.1 nmol/L range 94.3-562.4, p=0.001) compared to patients without TA-TMA (145.3 nmol/L, range 93.9-241.2). Patients with TA-TMA also had increased levels of C16 at day 14 (426.8 nmol/L, range 186.2-764.3) compared to patients with no TA-TMA (308.7 nmol/L, range 142.5-928.9, p=<0.0001) (Figure 2A). Similarly, levels of C18, C22 and C24:1 were significantly increased at baseline and on day 14 in patients with TA-TMA compared to patients without TA-TMA (Figures 2B-2D). We performed receiver operator characteristic (ROC) curve analysis for each ceramide species. Representative ROC analysis demonstrated an area under the curve (AUC) of 0.71 (p=0.001) for baseline C18 concentrations and an AUC of 0.72 (p<0.0001) for day 14 C16 concentrations (Figures 2E-2F). Baseline concentrations of NO in plasma were higher in patients with TA-TMA (19.1 nM), however did not reach statistical significance (p=0.07) (Figure 2G). Several baseline ceramide concentrations were significantly positively correlated with baseline NO levels (C16, r=0.49, p=0.01) (Figure 2H). Concentrations of long-chain and very long-chain ceramides are significantly higher at baseline and on day 14 from HSCT in patients diagnosed with TA-TMA. Differences in ceramide levels may be a result of alterations in NO-mediated signaling. Statins reduce circulating ceramides and might be effective TA-TMA prophylaxis in HSCT recipients with elevated ceramide levels prior to HSCT.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2023.12.042