A patient who underwent transplant with a liver that was preserved for three days outside the body using warm machine perfusion was healthy and leading a normal life a year later, say researchers from Switzerland. The procedure offers new hope for both rejected donors and recipients with poor prognoses.
The organ, weighing 1.7kg, was obtained on 19 May 2021.
The recipient was a 62-year-old patient with severe portal hypertension, advanced cirrhosis and recurrent hepatocellular carcinoma. Because the 29-year-old donor had invasive abdominal desmoid fibromatosis with chronic intra-abdominal abscesses, recurrent sepsis caused by multi-resistant bacteria (Candida glabrata, Candida dubliniensis and Enterococcus faecium) requiring long-term medications and total parenteral nutrition, and a 4cm tumour of unclear nature in segment 1 of the liver, the graft had been discarded by other centres.
The recipient experienced only minimal graft injury with normal bilirubin levels and a small release of liver enzymes within the first week after receiving the graft via ex situ normothermic preservation (peak alanine transaminase [ALT] 138 UL-1 and peak aspartate aminotransferase [AST] 309 UL-1), reported Dr Pierre-Alain Clavien, of University Hospital Zurich, and colleagues.
Endoscopic retrograde cholangiography at 11 months showed “a perfectly preserved intrahepatic biliary tree”, with lab tests that quickly normalised after a temporary stent was placed, the authors noted in Nature Biotechnology.
The patient experienced a full liver function recovery, with international normalised ratio returning to normal after four days.
“In our experience, the absence or very low degree of reperfusion injury seen in our transplant is observed only in living donation, where ‘close-to-perfect’ livers from healthy young donors are transplanted immediately as both donors and recipient are operated in parallel,” Clavien and team wrote.
“We think that this first transplantation success with an ex situ normothermic perfusion preserved organ can open new horizons in the treatment of many liver disorders,” they added.
“In the transplant community, we feel the urge daily to find a suitable organ for patients with a poor prognosis, and unfortunately there are still many patients dying awaiting an organ,” Clavien told MedPage Today. “This has led us to look for new ways to increase the donor pool and give these patients a chance.”
Current transplant practices provide a narrow window of opportunity (12 hours) to evaluate, transport and implant a donor graft, the authors noted.
Their previous pre-clinical work showed that normothermic perfusion could extend organ viability up to 10 days, but did not transplant the grafts into humans.
The team said baseline histology of the donated tumour in the graft was consistent with a non-malignant perivascular epithelioid tumour or angiomyolipoma without necrosis. After removal of the tumour and brief cold preservation with low-flow oxygenated perfusion at 6 to 8°C with cannulation of all vessels and the common bile duct, the graft was connected to the Wyss ex situ normothermic perfusion device at 37°C.
The device was primed with a blood-based perfusate targeting a hematocrit of 28-30%, which was supplemented with platelets and additives. After one hour of reperfusion, a biopsy showed no evidence of reperfusion injury or syndrome.
Liver function – as evidenced by factor V synthesis – continuously improved, from 33% at the start of perfusion to 54% within 24 hours.
During perfusion, broad-spectrum antibiotics were used. After organ recovery, elective surgery was performed with the graft, now weighing 1.3kg, within 60 minutes of disconnecting the machine on the fourth day of perfusion.
The liver graft had an immediate lactate clearance and increased bile production, in addition to low release of transaminases, which decreased after 24 hours (peak AST 791 UL-1 and peak ALT 587 UL-1).
The recipient developed acute kidney failure requiring short-term hemofiltration, “possibly related to a combination of hypovolemia and nephrotoxicity of one of the antibiotics (vancomycin) and hypoalbuminemia (14 gL-1)”, Clavien and team noted. Five days after surgery, a small anastomotic bile leak developed, which required a stent that was removed after four weeks. The patient was discharged 12 days after transplant on a reduced immunosuppressive regimen and returned to all usual activities within two months.
The number of hepatocytes increased by 2.3-fold from transplant to six weeks.
While “this inaugural case demonstrates the potential of preserving livers ex situ for several days”, additional research with longer follow-up is needed, Clavien and team noted.
Study details
Transplantation of a human liver following 3 days of ex situ normothermic preservation
Pierre-Alain Clavien, Philipp Dutkowski, Matteo Mueller, Dilmurodjon Eshmuminov, Lucia Bautista Borrego, Achim Weber, Beat Muellhaupt, Richard X. Sousa Da Silva, Brian R. Burg, Philipp Rudolf von Rohr, Martin J. Schuler, Dustin Becker, Max Hefti & Mark W. Tibbitt.
Published in Nature Biotechnology on 31 May 2022
Abstract
Current organ preservation methods provide a narrow window (usually <12 hours) to assess, transport and implant donor grafts for human transplantation. Here we report the transplantation of a human liver discarded by all centres, which could be preserved for several days using ex situ normothermic machine perfusion. The transplanted liver exhibited normal function, with minimal reperfusion injury and the need for only a minimal immunosuppressive regimen. The patient rapidly recovered a normal quality of life without any signs of liver damage, such as rejection or injury to the bile ducts, according to a 1-year follow up. This inaugural clinical success opens new horizons in clinical research and promises an extended time window of up to 10 days for assessment of viability of donor organs as well as converting an urgent and highly demanding surgery into an elective procedure.
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