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Keywords:

  • Auxiliary;
  • liver transplantation;
  • orthotopic;
  • reuse

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

We describe the first cases of reuse of auxiliary liver grafts for orthotopic transplantation in chronic liver disease. A reduced liver graft (segments 2, 3, half of 4) was first transplanted auxiliary for acute liver failure using a new technique. After regeneration of both native liver and graft, the auxiliary graft was removed and immunosuppression discontinued in the first recipients. After informed consent of donors and recipients, both auxiliary grafts were then orthotopically transplanted into second recipients. Both grafts function normally. Reuse of auxiliary grafts may help to reduce the shortage or liver grafts available for transplantation.


Background

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

The increasing shortage of liver grafts leads to a 15–20% mortality on the waiting list for liver transplantation. Several options to alleviate this shortage have been used, like nonheart-beating donors, marginal donors and better allocation systems. Still, the waiting lists are growing.

The usual way of liver transplantation is orthotopic liver transplantation (OLT), where a whole liver graft replaces the native liver. Around 10% of liver transplantations are performed for acute liver failure (ALF). Others and we have been using partial auxiliary liver transplantation (PALT) in ALF. Usually this was done as auxiliary partial OLT (APOLT): A partial graft is placed next to the partially resected native liver as a bridge to recovery. If the native liver regenerates (which is the case in 2/3 patients) the graft can be removed or left to atrophy when immunosuppressive medication is stopped.

We recently published a new technique of reno-portal anastomosis (REPALT) in the left upper abdomen next to the almost unresected native liver. The graft has a separate blood supply with this method. Rapid hypertrophy of the auxiliary grafts occurred due to regeneration (1).

Some cases of reuse of a liver graft from a recipient deceased after OLT have been described (2–8). We here describe the first two cases of orthotopic reuse of hypertrophied partial liver grafts for recipients with chronic liver disease donated by surviving recipients of PALT for ALF whose native liver regenerated. The use of PALT with REPALT in ALF wherever possible, followed by reuse of the hypertrophied graft for OLT in second recipients with chronic liver disease can potentially increase the donor pool.

Methods

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

First recipients

The reduced liver (segments 2, 3, half of 4 with a weight of 550 grams) from a heart-beating brain-dead multi-organ 80 kg donor was first transplanted auxiliary to the native liver of a 25-year-old 42 kg woman with ALF due to 30 days of tuberculostatic therapy with isoniazide and rifampin for proven axillary lymph node tuberculosis, as described (9). She fulfilled the King's College Hospital criteria for transplantation, was in coma with elevated intracranial pressure and hepatorenal syndrome, ventilated, on inotropic medication, and treated with continuous veno-venous haemofiltration (CVVH) with molecular absorbent recirculating system (MARS) and hypothermia. Cold ischemia time (CIT) was 682 min and warm ischemia time (WIT) was 40 min. Arterial reconstruction was performed with a donor iliac graft to the aorta; portal reconstruction end-to-side to recipient portal vein; venous reconstruction by end-to-side caval anastomosis after left-sided resection of segment 1; biliary reconstruction by choledocho-gastrostomy. Immunosuppression was with tacrolimus, prednisolone and basiliximab. Within 1 day relaparotomy was necessary to remove a partial portal vein thrombosis of the graft, probably caused by low flow due to competition for portal blood between native liver and graft. Allthough there was no portal vein kinking, revision of the anastomosis was performed after thrombectomy and heparin infusion was started. Histology of the resected native liver segment 1 showed multilobular necrosis. Ethambutol and levofloxacin were given as nonhepatotoxic tuberculostatics. The auxiliary graft functioned well with normalization of liver function including INR and bilirubin. Hepatorenal syndrome and coma resolved immediately after APOLT. Mebrofenin scintigraphy (HIDA) on day 3 showed a functioning graft and virtually no uptake and excretion in the native liver. On day 18 posttransplant the liver histology from the graft was normal with some granulocytic infiltration. On day 27 after transplantation the native liver had regenerated sufficiently, as shown by histology, CT volumetry (1100 mL) and HIDA to allow resection of the hypertrophied auxiliary graft. The graft had a weight of 1150 g at resection. Immunosuppression was discontinued. At that time work-up for a fever only disclosed a primary CMV-infection with positive plasma CMV-DNA. PCR for TBC was negative on native liver and auxiliary graft. The axillary lymph node was not detectable anymore on CT-scan and palpation. CMV-DNA and fever disappeared with 2 weeks of i.v. gancyclovir. Ethambutol and pyrazinamide were given for another 9 months after removal of the graft, then stopped. After ethical committee approval and informed consent from both this PALT recipient and potential second recipient the partial liver graft was removed from the first recipient and then orthotopically transplanted into a second recipient. This first recipient is in good health 2 years later without recurrence of tuberculosis.

A 37-year-old multiparous female with ALF due to acute fatty liver of pregnancy (AFLP) at 37 weeks gestation worsened with increasingly disturbed clotting, hyperbilirubinemia and coma with brain oedema in the 3 days after delivery of the intrauterinely deceased child. She fulfilled the King's College criteria for liver transplantation. After stabilization with CVVH, MARS and hypothermia PALT was performed with segments 2, 3 and half of 4 (weight 456 g) of a brain-dead post-mortal donor liver. We did this using the technique as described above, but with the portal vein anastomosed to the left renal vein that was disconnected from the caval vein and the hepatic artery conduit anastomosed end-to-side to the aorta just below the diaphragm. The surgical technique of PALT with REPALT (Figure 1) was as follows:

image

Figure 1. Surgical technique of auxiliary liver transplantation with renoportal anastomosis (REPALT). I: Partial resection of segment 1 of the native liver for venous access to the caval vein in orthotopic position (with the graft in heterotopic position). II, III, IV: Auxiliary graft. (1) Tool-kit-donor common and external iliac artery, (2) Left hepatic artery, (3) Left portal branch (portal vein), (4) Tool-kit-donor common and external iliac vein, (5) Left renal vein, (6) Coeliac trunk, (7) Left hepatic bile duct on stomach, (8) Left hepatic vein, (9) Inferior caval vein, (10) Aorta. Drawn by Jan-Hein van Dierendonck.

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  • (i) 
    Partial resection of segment 1 of the native liver for venous access to the caval vein in orthotopic position (with the graft in heterotopic position).
  • (ii) 
    End-to-side anastomosis of the left hepatic vein of the graft to the recipient caval vein just below the level of recipients left hepatic vein.
  • (iii) 
    Portal venous inflow from the recipient's left renal vein. The portal vein from the graft was first lengthened utilizing donor iliac vein, positioned dorsal of the pancreas and anastomosed end-to-end to the left renal vein.
  • (iv) 
    Arterial anastomosis with the iliac conduit of the donor, previously anastomosed end-to-side to the recipient's aorta above the celiac trunk.
  • (v) 
    Biliary drainage by end-to-side anastomosis between the donor common bile duct and the anterior stomach wall of the recipient.

We recently described this technique of REPALT in detail (1). CIT was 623 min, WIT 50 min. Immunosuppression was with tacrolimus, basiliximab and prednisolone. The resected native liver segment 1 histology confirmed AFLP. There was immediate graft function, and within a day patient was ectubated. After 1 more week on CVVH there was restoration of renal function and patient left the intensive care unit. Liver biopsies from the native liver showed rapid normalization of histology within 1 month, the size of the native liver on CT did not change as expected in AFLP. The graft hypertrophied to 1066 mL on day 4 and then remained stable at 1042 mL day 15 on CT volumetry (Vitrea, Vital Images Inc., Minnetonka, MN) and HIDA. Graft volume at day 26 after REPALT, 4 days before transplantectomy had not changed when ultrasound-guided liver biopsies were obtained: Histology of the native liver still showed some steatosis, graft histology was normal. The initial critical illness neuropathy fully resolved.

After informed consent of this REPALT recipient and the potential second recipient the graft, which then had a weight of 1050 g, was removed 1 month after REPALT and reused for OLT in the second recipient. All previous anastomosis were dismanteled, primary closure of caval vein, aorta and stomach was performed. The resected graft was perfused with UW and cold-stored. The left renal vein in this first recipient was reanastomosed to the caval vein and scintigraphy revealed normal function of the left kidney.

We successfully performed a third REPALT in ALF due to fulminant hepatitis B similarly, but this patient had slower regeneration of the native liver as shown before in hepatitis B, while graft regeneration was as rapid as in the second patient described above. After full regeneration of the native liver, a year after REPALT, laparotomy was performed with the aim of removing and possibly reusing the graft. In this case, removal of the graft was considered too risky due to adherence of the graft to surrounding tissues, and the graft was left in situ to atrophy with decreasing immunosuppression. This patient is also doing well off immunosuppression now, with normal liver and kidney function and normal renal scintigraphy.

Results

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Second recipients

The second recipient of OLT with the first partial auxiliary graft was a 17-year-old 50 kg woman with Child-Pugh stage C cirrhosis due to autoimmune hepatitis (AIH), who due to her short stature (160 cm), low body weight and type-B blood group had a very low chance of receiving a regular liver graft in time. There was no living-related donor. First WIT was 14 min, CIT was 210 min and second WIT was 36 min. End-to-side left hepatic vein to caval, end-to-end porto-portal, end-to-end hepatic artery and end-to-end common bile duct anastomoses were performed. Immunosuppression was with tacrolimus, basiliximab and prednisolone. Despite the relatively short ischemia times initial poor function developed, then function normalized. Because of the findings in the first recipient of this graft, i.v. gancyclovir was given for 2 weeks, ethambutol and pyrazinamide were given for 8 weeks. Patient was discharged home on day 64. No tuberculosis was detected. An episode of acute cellular rejection was treated with methyl-prednisolone. At 6 month after partial OLT when patient resumed school, a liver biopsy from segment 3 showed only minimal changes. At 12 months a biopsy-proven mild recurrence of AIH was treated by adjusting immunosuppression and at 2 years noncompliance was managed by education. There were no further complications. Two years after transplantation alkaline phosphatase and gammaglutamyltransferase are twice the upper limit of normal, while INR, bilirubin, aminotransferases, albumin and creatinin are within normal ranges and patient has no complaints and continues her education.

The second graft, removed after REPALT for AFLP, was reused for OLT in a 59-year-old male recipient with cryptogenic Child-Pugh stage C cirrhosis, heterozygous for the C282Y haemochromatosis mutation, and a 5 cm hepatocellular carcinoma close to the diaphragm that could only be partially treated by radiofrequency ablation 6 months prior to transplantation. This reuse of the graft shortened waiting time by approximately a year for this patient, possibly improving chances of tumour-free survival. End-to-side left hepatic vein to caval vein, end-to-end porto-portal, end-to-end hepatic artery and end-to-end common bile duct anastomoses were performed. Immediate graft function was excellent. Apart from Escherichia Coli sepsis on day 16 after removal of a biliary stent, treated with i.v. antibiotics, patient was discharged home on day 29 with normal liver function. In the first 2 years, he underwent endoscopic dilatations of a donor common bile duct stricture. He recently was successfully treated with voriconazole for an Aspergilloma and underwent temporary dialysis after a tacrolimus intoxication. He now is in excellent condition without signs of tumour recurrence more than 2 years after transplantation.

Both ‘living unrelated donors’, the first recipients of the auxiliary grafts, are living a normal life without medication. The impossibility of removing the graft in the third auxiliary graft REPALT recipient suggests that timing may be critical for graft removal and reuse.

Discussion

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Currently between 10 and 20% of the recipients in the Eurotransplant area die before a liver graft becomes available. Living donation is not always an option. Grafts from nonheart-beating donors or from marginal donors, split grafts, improved allocation and alternatives to transplantation all may reduce death on the waiting list to some degree. Some cases of reuse of a liver graft from a recipient deceased after OLT have been described (2–8). This is the first description showing that orthotopic reuse of a partial auxiliary liver graft is feasible using a new technique. With this reuse two second recipients were transplanted. Since rapid regeneration occurs, especially with the new REPALT technique we described recently, the volume of the graft almost had the volume of a whole liver (1). Auxiliary liver transplantation is used more often than previously for ALF with acceptable results (even from a nonheart-beating donor or from a living donor) (10–14). Therefore REPALT with reuse of these liver grafts may be considered more often in order to help alleviate organ shortage. Initially auxiliary graft removal is easy. The renal vein is then reanastomosed to the caval vein. After some months, graft removal may become more difficult as in our third auxiliary graft recipient.

Auxiliary liver transplantation is feasible in haemodynamicaly stable patients with ALF and sufficient chances for native liver regeneration. The percentage of remaining hepatocytes is not predictive for the chances of regeneration, while nondrug aetiology and younger age may be (15). Despite the fact that in selected cases patient survival is similar after OLT and APOLT in ALF, while two-thirds of the surviving patients are off immunosuppression within 1 year, portal vein thrombosis and initial poor graft function have been problems inherent to APOLT with porto-portal anastomosis, (14,16), Our first auxiliary graft recipient had this complication. Portal vein thrombosis in APOLT occurs despite techniques trying to reduce the incidence, like banding of the portal vein, and is probably caused by a low-flow state when the portal blood flow is divided to serve both native liver and graft (17). For the second auxiliary graft recipient we therefore modified the portal vein anastomosis: after disconnection from the caval vein, the left renal vein was anastomosed to the graft portal vein. This reno-portal venous anastomosis also circumvents the possible problem of hyper-perfusion with hepatic damage that may occur when portal arterialisation is carried out, which is another way to prevent portal vein thrombosis in PALT (18,19). With the REPALT technique graft function was excellent and grafts hypertrophied rapidly with normal histology.

Since the auxiliary graft was placed in the left upper abdomen, the hepatic artery is anastomosed directly or via an iliac conduit to the infradiaphragmic aorta. This may also reduce the incidence of hepatic artery thrombosis, which was also seen often after APOLT. With higher arterial pressure porto-arterial reflux as another cause of hepatic artery thrombosis after APOLT is less likely to occur (20).

Interestingly, especially the second graft described with REPALT showed immediate function as evidenced on HIDA and both showed impressive growth in size within 1 month. It was previously thought that growth factors in portal blood were needed for such regeneration. Apparently, similar or other growth factors are present in renal venous blood in a patient with liver failure. Further study of this phenomenon may shed new light on liver regeneration.

With our new REPALT technique in combination with reuse of the graft for OLT in a second recipient, potentially two recipients can be transplanted serially with half a liver. Even more recipients might benefit if a split graft is used for REPALT. With REPALT the thrombotic and perfusion problems that were frequently seen in APOLT are prevented in REPALT by a separate blood supply, using the left renal vein to portal vein anastomosis. This probably contributed to rapid regeneration of the graft. The absence of significant resection (only segment 1) of the native liver may contribute to more rapid recovery of native liver function.

These cases demonstrate that orthotopic reuse of a temporary auxiliary liver graft for a patient with chronic liver disease is feasible and can provide excellent outcome. A large size of the graft on CT together with normal histology and liver function and normal HIDA at the time of explantation allow reuse for OLT.

Since about 10% of liver transplantations are performed for ALF, wider application of auxiliary liver transplantation with REPALT with reuse of the graft after regeneration of the native liver may help to reduce the shortage or liver grafts available for transplantation.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

We thank Sandra Arends, M.D., Ph.D., internist and consultant in infectious disease, for her important help in managing and preventing tuberculosis in the first donor and recipient.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  • 1
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  • 20
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