Low Serum Levels of (Dihydro-)Ceramides Reflect Liver Graft Dysfunction in a Real-World Cohort of Patients Post Liver Transplantation
Abstract
:1. Introduction
2. Results
2.1. Patients’ Characteristics
2.2. Low Serum Long and Very Long Chain (Dihydro-) Ceramides Associate with History of Graft Rejection and Ischemic Type Biliary Lesions (ITBL)
2.3. Tacrolimus Based Immunosuppressive Therapy Associates with Upregulated Serum Cer Levels
2.4. Analyses of Serum Cer’s Concerning Pre-OLT Hepatopathy, HCC, Donors’ Characteristics and Time Between OLT and Blood Withdrawal
3. Discussion
4. Patients and Methods
4.1. Patients’ Selection
4.2. Determination of Sphingolipid Concentrations by High-Performance Liquid Chromatography Tandem Mass Spectrometry
4.3. Statistical Analyses
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Parameters | Patients (n = 149) |
---|---|
Age, years; mean (range) | 56 (21–79) |
Gender | |
Female, n (%) | 55 (37%) |
Male, n (%) | 94 (63%) |
Body mass index; mean (range) | 26 (16.4–46.5) |
Blood type A/B/AB/0, n (%) | 57 (38%)/23 (15%)/7 (4.6%)/39 (26%) |
ALT, IU/L; mean (range) | 30 (7–132) |
AST, IU/L; mean (range) | 30 (13–100) |
GGT, IU/L; mean (range) | 89 (8–1525) |
Bilirubin, mg/dL; mean (range) | 0.8 (0.1–19) |
Creatinine, mg/dL; mean (range) | 1.3 (0.64–9.76) |
Triglyceride, mg/dL; mean (range) | 134 (40–411) |
Cholesterol, mg/dL; mean (range) | 178 (38–331) |
Albumin, mg/dL; mean (range) | 4.3 (3–4.9) |
International normalized ratio; mean (range) | 1.07 (0.84–3.38) |
Tacrolimus though level, ng/ml; mean (range) of 133 patients | 5.9 (2.4–23.1) |
Aetiology pre-OLT chronic liver disease | |
Hepatitis B, n (%) | 18 (12%) |
Hepatitis B/D coinfection, n (%) | 5 (3%) |
Hepatitis C, n (%) | 34 (22.8%) |
Hepatitis B/C coinfection, n (%) | 7 (4.7%) |
Alcohol intake, n (%) | 35 (23%) |
Non-alcoholic steatohepatitis, n (%) | 1 (0.7%) |
Primary sclerosing cholangitis, n (%) | 5 (3.6%) |
Primary biliary cholangitis, n (%) | 4 (2.7%) |
Cryptogenic, n (%) | 17 (11%) |
Other, n (%) | 32 (21.5%) |
HCC pre-OLT, n (%) | 43 (28.9%) |
CMV-IgG-antibody positive, n (%) | 109 (73%) |
Graft rejection, n (%) | 29 (19.5%) |
Ischemic type biliary lesions, n (%) | 15 (10%) |
Immunosuppressive therapy | |
Tacrolimus, n (%) | 133 (89%) |
Mycophenolate-mofetil, n (%) | 79 (53%) |
Cyclosporine A, n (%) | 8 (5%) |
mTor-Inhibitors, n (%) | 12 (8%) |
Steroids, n (%) | 16 (10.7%) |
Basiliximab, n (%) | 2 (1%) |
Donors’ gender | |
Female, n (%) | 50 (33.5%) |
Male, n (%) | 62 (41.6%) |
Not applicable, n (%) | 37 (24.8%) |
Grafts’ age, years; mean (range) | 58 (17–89) |
AB0-matching: identical/compatible/incompatible, n (%) | 114 (77%)/10 (6.7%)/0 (0%) |
SL | Patients’ Age at BW | AST | ALT | GGT | Chol | TG | Tacrolimus Though Level | Grafts’ Age at BW | Time Between OLT and BW |
---|---|---|---|---|---|---|---|---|---|
Sphingosine | 0.149 | 0.030 | 0.147 | 0.062 | 0.120 | 0.095 | −0.0001 | 0.104 | −00.031 |
Sphinganine | 0.047 | 0.036 | 0.194 * | 0.049 | 0.082 | 0.065 | −0.039 | 0.114 | −0.031 |
S1P | −0.014 | 0.069 | 0.171 * | 0.059 | 0.225 ** | 0.114 | 0.027 | −0.111 | −0.014 |
dhS1P | −0.046 | 0.104 | 0.211 ** | 0.049 | 0.211 ** | 0.165 * | 0.037 | −0.040 | 0.030 |
C24Cer | 0.214 ** | −0.296 *** | −0.050 | −0.145 | 0.606 *** | 0.429 *** | 0.159 | −0.110 | −0.186 * |
C16Cer | 0.059 | 0.065 | 0.016 | 0.164 * | 0.205 ** | 0.124 | −0.079 | 0.081 | −0.199 * |
C14Cer | 0.069 | 0.037 | 0.125 | 0.101 | 0.284 *** | 0.129 | −0.014 | −0.018 | −0.096 |
C18Cer | 0.308 *** | −0.029 | 0.115 | 0.203 * | 0.427 *** | 0.455 *** | −0.051 | −0.086 | −0.142 |
C20Cer | 0.306 *** | −0.215 ** | −0.071 | 0.060 | 0.396 *** | 0.418 *** | 0.007 | −0.154 | −0.167 * |
C18:1Cer | 0.031 | −0.041 | −0.0003 | 0.022 | 0.217 ** | 0.136 | 0.008 | 0.075 | −0.094 |
C24:1Cer | 0.291 *** | −0.153 | −0.004 | 0.082 | 0.401 *** | 0.444 *** | 0.108 | −0.197 * | −0.208 * |
C16DHC | −0.010 | 0.142 | 0.076 | 0.137 | 0.039 | 0.040 | −0.082 | 0.106 | −0.072 |
C18DHC | 0.273 *** | −0.034 | 0.078 | 0.142 | 0.284 *** | 0.377 *** | −0.071 | 0.030 | −0.093 |
C24DHC | 0.161 | −0.104 | 0.101 | −0.055 | 0.529 *** | 0.313 *** | 0.062 | 0.001 | −0.130 |
C24:1DHC | 0.199 * | 0.109 | 0.213 ** | 0.186 * | 0.317 *** | 0.272 *** | −0.063 | 0.033 | −0.040 |
Univariate Analysis | Multivariate Analysis | |||
---|---|---|---|---|
Variable | p Value | OR (95% CI) | p Value | OR (95% CI) |
Age | 0.919 | 0.997 (0.942–1.055) | ||
Gender patient | 0.339 | 1.704 (0.572–5.081) | ||
Gender donor | 0.938 | 0.959 (0.332–2.770) | ||
ITBL | 0.388 | 1.902 (0.441–8.194) | ||
HCC pre-OLT | 0.353 | 0.581 (0.185–1.828) | ||
Tacrolimus intake | 0.207 | 0.296 (0.045–1.965) | ||
ALT | 0.091 | 0.980 (0.957–1.003) | ||
AST | 0.138 | 0.973 (0.938–1.009) | ||
GGT | 0.892 | 1.000 (0.997–1.003) | ||
Sphingosine-1-phosphate | 0.749 | 0.999 (0.993–1.005) | ||
Sphinganine | 0.932 | 0.992 (0.823–1.195) | ||
Sphinganine-1-phosphate | 0.449 | 0.993 (0.973–1.012) | ||
C18Cer | 0.475 | 1.009 (0.985–1.033) | 0.072 | 0.973 (0.945–1.002) |
C18:1Cer | 0.571 | 1.016 (0.962–1.072) | ||
C20Cer | 0.225 | 1.017 (0.990–1.045) | ||
C24Cer | 0.048 | 1.001 (1.000–1.002) | 0.039 | 1.001 (1.000–1.002) |
C18DHC | 0.073 | 1.084 (0.992–1.183) | 0.035 | 1.132 (1.009–1.269) |
C24:1DHC | 0.113 | 1.018 (0.994–1.043) | ||
Age | 0.311 | 1.032 (0.971–1.097) | ||
Gender patient | 0.292 | 2.000 (0.551–7.256) | 0.083 | 3.718 (0.842–16.424) |
Gender donor | 0.863 | 0.894 (0.251–3.190) | ||
Graft rejection | 0.388 | 1.902 (0.441–8.195) | ||
HCC pre-OLT | 0.818 | 0.857 (0.230–3.189) | ||
Tacrolimus intake | 0.933 | 2.741×104 (0.000–3.39×10107) | ||
ALT | 0.204 | 0.984 (0.959–1.009) | ||
AST | 0.294 | 0.979 (0.941–1.019) | ||
GGT | 0.003 | 0.994 (0.989–0.998) | 0.006 | 0.994 (0.989–0.998) |
C16Cer | 0.931 | 1.001 (0.982–1.020) | ||
C18DHC | 0.025 | 1.158 (1.019–1.316) | 0.042 | 1.172 (1.006–1.366) |
C24DHC | 0.082 | 1.024 (0.997–1.052) | ||
C24:1DHC | 0.375 | 1.012 (0.986–1.040) |
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Mücke, V.T.; Gerharz, J.; Jakobi, K.; Thomas, D.; Ferreirós Bouzas, N.; Mücke, M.M.; Trötschler, S.; Weiler, N.; Welker, M.-W.; Zeuzem, S.; et al. Low Serum Levels of (Dihydro-)Ceramides Reflect Liver Graft Dysfunction in a Real-World Cohort of Patients Post Liver Transplantation. Int. J. Mol. Sci. 2018, 19, 991. https://doi.org/10.3390/ijms19040991
Mücke VT, Gerharz J, Jakobi K, Thomas D, Ferreirós Bouzas N, Mücke MM, Trötschler S, Weiler N, Welker M-W, Zeuzem S, et al. Low Serum Levels of (Dihydro-)Ceramides Reflect Liver Graft Dysfunction in a Real-World Cohort of Patients Post Liver Transplantation. International Journal of Molecular Sciences. 2018; 19(4):991. https://doi.org/10.3390/ijms19040991
Chicago/Turabian StyleMücke, Victoria Therese, Janis Gerharz, Katja Jakobi, Dominique Thomas, Nerea Ferreirós Bouzas, Marcus Maximilian Mücke, Sven Trötschler, Nina Weiler, Martin-Walter Welker, Stefan Zeuzem, and et al. 2018. "Low Serum Levels of (Dihydro-)Ceramides Reflect Liver Graft Dysfunction in a Real-World Cohort of Patients Post Liver Transplantation" International Journal of Molecular Sciences 19, no. 4: 991. https://doi.org/10.3390/ijms19040991