The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.
The last decade has seen a considerable rise in ventricular assist device (VAD) support as bridge to heart transplant (HT) coupled with increasing transplantation for single ventricle congenital heart disease (SV CHD). Neurologic events (NE) are common in both patient groups. We sought to describe NE before and after HT in the modern era among children and young adults. Methods: We performed a single center retrospective review of patients who underwent HT between 1/2013 and 4/2020. NE included seizures, stroke, subdural hemorrhage (SDH) and posterior reversible encephalopathy syndrome (PRES). Clinical characteristics were compared between patients with and without post-HT NE. Results: Overall 163 patients met study criteria, of whom 54 (33%) had a pre-HT NE and 29 (18%) had at least one post-HT NE. Post-HT NE included seizures in 23/163 (14%), strokes in 10/163 (6%), SDH in 9/163 (6%), and PRES in 7/163 (4%). Median time from HT to first post-HT NE was 24 days (IQR 3, 277). Post-HT NE were associated with SDH (6/29 (21%) vs 9/134 (7%), p=0.03), pre-HT ICU admission (11/29 (38%) vs 21/ 134 (16%), p=0.009), and allograft ischemic time (250 min (IQR 221, 224) vs 223 min (IQR 189, 250), p=0.001), and not with pre-HT NE, SV CHD, or VAD support. ICU admission was an independent predictor of post-HT NE on multivariate analysis (hazard ratio 2.87 (CI 1.09, 7.62), p=0.03). Post-HT NE were associated with significantly decreased survival. Conclusion: Post-HT NE are common in children and young adults and occur early post-HT. They are associated with ICU status at time of HT, and not with SV CHD or pre-HT VAD support. Post-HT neurologic events portend a poor prognosis, with 50% mortality by 5 years.
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