Normothermic machine perfusion reduces bile duct injury and improves biliary epithelial function in rat donor livers

Abstract

Bile duct injury may occur during liver procurement and transplantation, especially in livers from donation after circulatory death (DCD) donors. Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury compared to static cold storage (SCS). However, it is unknown whether NMP provides better preservation of bile ducts. The aim of this study was to determine the impact of NMP on bile duct preservation in both DCD and non-DCD livers. DCD and non-DCD livers obtained from Lewis rats were preserved for 3 hours using either SCS or NMP, followed by 2 hours ex vivo reperfusion. Biomarkers of bile duct injury (gamma-glutamyltransferase and lactate dehydrogenase in bile) were lower in NMP-preserved livers compared to SCS-preserved livers. Biliary bicarbonate concentration, reflecting biliary epithelial function, was 2-fold higher in NMP-preserved livers (P < 0.01). In parallel with this, the pH of the bile was significantly higher in NMP-preserved livers (7.63 6 0.02 and 7.74 6 0.05 for non-DCD and DCD livers, respectively) compared with SCS-preserved livers (7.46 6 0.02 and 7.49 6 0.04 for non-DCD and DCD livers, respectively). Scanning and transmission electron microscopy of donor extrahepatic bile ducts demonstrated significantly decreased injury of the biliary epithelium of NMP-preserved donor livers (including the loss of lateral interdigitations and mitochondrial injury). Differences between NMP and SCS were most prominent in DCD livers. Compared to conventional SCS, NMP provides superior preservation of bile duct epithelial cell function and morphology, especially in DCD donor livers. By reducing biliary injury, NMP could have an important impact on the utilization of DCD livers and outcome after transplantation.

Reply to: “The rescue of DCD rodent livers grafts: Is there HOPE?”

“…This has led various learned societies to re-define ARF as acute kidney injury (AKI), incorporating even small changes in serum creatinine either in absolute or percentage terms in the diagnostic criteria [4][5][6]. The degree of AKI severity is also defined by stages [4][5][6]. The most commonly reported classification used to diagnose AKI is that of the Acute Kidney Injury Network (AKIN), which set forth specific serum creatinine and urine output changes to define stages of AKI, without setting a fixed serum creatinine level in its diagnostic criteria [5].…”

“…More recently, it has been recognized in non-cirrhotic patients that smaller increases in serum creatinine also have a negative impact on survival [3]. This has led various learned societies to re-define ARF as acute kidney injury (AKI), incorporating even small changes in serum creatinine either in absolute or percentage terms in the diagnostic criteria [4][5][6]. The degree of AKI severity is also defined by stages [4][5][6].…”

“…Both groups report a haematocrit of approximately 20%, insulin, heparin and nutritions were similarly as in our experiments. Adding of Williams E medium in normothermic experiments is based on recent experiments by Op den Dries et al in rats [4]. Both perfusates have been tested initially in healthy normal rat livers (no injury group) and achieved minimal AST release, sufficient bile flow, tissue ATP and 100% animal survival, thus demonstrating sufficient energy supply during normothermic perfusion experiments (Fig.…”

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients

“…In normothermic machine perfusion, the liver is kept viable ex situ by perfusion with warm oxygenated blood. 395,399 Mild hypothermia may lower the rate of DGF in kidney transplantation recipients, especially if high-risk donors, such as donors with a high KDPI, are used. 367 In a study of hypothermic machine perfusion in 31 adults receiving livers from donors with a high KDPI, EAD was lower in this group (19%) compared to the static cold storage control group (30%), with significantly less biliary complications (4 vs 13; P = 0.016).…”

“…A recent study in rats reported that normothermic machine perfusion provided better preservation of bile duct epithelial cell function and morphology in both DCD, and non-DCD livers (after 3 hours, followed by 2 hours ex vivo reperfusion), compared with static cold storage. 399 Another study using continuous normothermic machine perfusion from procurement to transplantation in pig liver transplants resulted in good posttransplantation survival, even after 20 hours of warm preservation. 400 The use of continuous perfusion is thought to be necessary because normothermic Considerations for managing EAD and nonanastomotic BS in liver transplantation 32,384,387,388,392,395,[397][398][399][400][401][402] …”