Mounting evidence supports the benefits of machine perfusion for preservation of liver grafts. Thus, machine perfusion is a promising strategy to expand the donor pool by reconditioning and assessing viability of DCD, elderly and steatotic grafts during the preservation period. Additionally, machine perfusion will serve as a platform to facilitate graft intervention and modification to further optimize marginal grafts.

Ex situ machine perfusion is a promising technology to help improve organ viability prior to transplantation. However, preclinical studies using discarded human livers to evaluate therapeutic interventions and optimize perfusion conditions are limited by significant graft heterogeneity. In order to improve the efficacy and reproducibility of future studies, a split-liver perfusion model was developed to allow simultaneous perfusion of left and right lobes, allowing one lobe to serve as a control for the other. Eleven discarded livers were surgically split, and both lobes perfused simultaneously on separate perfusion devices for 3 h at subnormothermic temperatures. Lobar perfusion parameters were also compared with whole livers undergoing perfusion. Similar to whole-liver perfusions, each lobe in the split-liver model exhibited a progressive decrease in arterial resistance and lactate levels throughout perfusion, which were not significantly different between right and left lobes. Split liver lobes also demonstrated comparable energy charge ratios. Ex situ split-liver perfusion is a novel experimental model that allows each graft to act as its own control. This model is particularly well suited for preclinical studies by avoiding the need for large numbers of enrolled livers necessary due to the heterogenous nature of discarded human liver research.

NMP is a multifunctional tool with potential to transform liver preservation and the field of transplantation. Large clinical trials are necessary to optimize perfusion protocols, clarify indications for NMP therapy and justify use as the standard preservation modality.

Cellular rejection of liver transplant allografts remains a concern despite immunosuppressant use. Existing transplant biomarkers are often not sensitive enough to detect acute or chronic rejection at an early enough stage to allow successful clinical intervention. We herein developed a cell-based sensor that can potentially be used for monitoring local events following liver transplantation. Utilizing a machine perfusion system as a platform to engraft the cells into a donor liver, we effectively established the biocompatibility of the biosensor cells and confirmed efficient delivery of cells distributed throughout the organ. This work proves an innovative concept of integrating synthetic reporter cells ex vivo into organs as a transplant-within-a-transplant during functional organ preservation with a vision to use cell biosensors as a broad way to monitor and treat tissue transplants.

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A 76-year-old woman presented with worsening fasting hyperglycemia on routine blood sugar measurement, previously well-controlled on Metformin, requiring initiation of insulin. Her medical history included type 2 diabetes mellitus, hypertension, and aortic stenosis. Over the next few weeks, she developed bilateral upper and lower extremity proximal muscle weakness, episodes of confusion, rapid weight loss and increasing lower extremity edema. She did not have typical Cushingoid features of moon facies, easy bruising, centripetal obesity, abdominal striae, dorsocervical fat padding, or hyperpigmentation. Laboratory data revealed severe hypokalemia, elevated cortisol of 138 (3.7–19.4 ug/dL) and ACTH of 368 (6–50 pg/mL) consistent with ACTH-dependent Cushing’s syndrome. She was hospitalized for emergent therapy with etomidate infusion, potassium supplementation, and started on spironolactone. 24-hour urinary analysis demonstrated elevated catecholamines and metanephrines: epinephrine 552 (2–16 mcg/g cr), norepinephrine 1881 (7-5 mcg/g cr), metanephrine 4095 (21–153 mcg/g cr), normetanephrine 3920 (108–524 mcg/g cr). CT abdomen showed 3.8 cm mass in the left adrenal gland with enhancing walls and central hypoattenuation and a normal contralateral adrenal gland. MR brain showed a partial empty sella without any mass. 123I-metaiodobenzylguanidine scintigraphy showed uptake in the left adrenal mass. Once cortisol was reduced to <25 ug/dL, she was transitioned from etomidate to metyrapone; alpha-methyltyrosine and prazosin was also begun. Following left laparoscopic adrenalectomy, ACTH decreased to <5 pg/mL confirming that the pheochromocytoma was the source of ectopic Cushing’s. Gross examination of the mass was notable for a spongy, tan, roughly spherical medullary neoplasm (3 cm in diameter) with a rim of brown and focally yellow adrenal cortex up to 4 mm thick. Marked diffuse adrenal cortical hyperplasia was noted. The tumor showed varied growth patterns, including solid areas and spongy, angioma-like areas with prominent small blood vessels. Immunohistochemical staining was positive for somatostatin receptor 2A, tyrosine hydroxylase and ACTH in tumor cells and negative for T-PIT. She was discharged on replacement hydrocortisone therapy, minimal insulin for diabetes and has shown substantial clinical improvement. Cushing’s syndrome due to ectopic ACTH-producing pheochromocytoma is rare. Worsening hyperglycemia in the presence of hypertension, even without typical clinical findings of Cushing’s, should prompt further hormonal work up. The absence of the transcription factor TPIT, which is a lineage determinant for pituitary corticotrophs, suggests that novel pathways are involved in differentiation of cells that produce ectopic ACTH.