Living-donor liver transplantation European experiences

Transcription

1 Nephrol Dial Transplant (2004) 19 [Suppl 4]: iv16 iv21 doi: /ndt/gfh1036 Living-donor liver transplantation European experiences Utz Settmacher, Tom Theruvath, Andreas Pascher and Peter Neuhaus Department of General, Visceral and Transplantation Surgery, Charite, Virchow Clinic, Humboldt University of Berlin, Germany Abstract To overcome the problem of organ shortage in recent years, liver transplantation from a living donor has been established. From a surgical standpoint, split liver transplantation and living-donor liver transplantation (LRLTx) are very complex surgical procedures requiring meticulous surgical techniques. LRLTx was first developed and performed in Asia and the USA. In the beginning of the 1990s, LRLTx was introduced in Europe. In Europe, 46 of 118 registered transplant centres had already performed LRLTx in December Up to this time point, more than 800 LRLTx were performed since Medical discussions in the field of LRLTx include the need for high qualitiy procedures, simplifying donor evaluation, optimizing surgical techniques and immunosuppression, all of which are current problems. The perioperative morbidity of the donor including all minor complications is stated to be 10 25%. Biliary complications of 5 10% are the major portion. The results of LRLTx for paediatric and adult recipients are comparable. The perioperative complication rate is slightly higher in LRLTx than after cadaver transplantation. This can be explained by the complexity of the surgical intervention with technical complications and the limited experience so far. Other reasons that can be ascertained are extended indications with higher incidence of tumour recurrence and infectious complications in these recipients. In recent years, LRLTx has emerged as a clinically safe alternative to cadaver transplantation in many cases and has further extended the donor pool. LRLTx has been shown to be a good option for patients with liver disease in which a long waiting time is not permitted. Keywords: actual problems; Europe; liver transplantation; living donor; outcome Correspondence and offprint requests to: Professor Dr Utz Settmacher, Department of General, Visceral and Transplantation Surgery, Charité, Virchow Clinic, Humboldt University of Berlin, Augustenbuger Platz 1, Berlin, Germany. utz. settmacher@charite.de Introduction Liver transplantation (LTx) has been established as the only definitive therapy in many cases of end-stage liver disease. Clinical long-term outcome was improved by optimizing surgical techniques and by the introduction of newer immunosuppressive agents such as cyclosporin A and tacrolimus (FK 506). This course led to a rapid increase in the demand for this procedure in potential liver recipients throughout the 1980s, exceeding by far the numbers of potential donor organs. To overcome the problem of organ shortage, not only the introduction of split-liver transplantation and acceptance of marginal allografts for transplantation, but in recent years also LTx from a living donor was established. These viable options have improved in recent years, so that results are comparable to those of cadaveric liver transplants. From a surgical standpoint, split-liver transplantation and living-donor liver transplantation (LRLTx) are very complex surgical procedures requiring meticulous surgical techniques. LRLTx should be performed with maximum precaution, in order to keep complications, especially for the donor, as low as possible. To accomplish this, a multilevel donor evaluation programme has been introduced for the potential donor, in order to estimate the organ quality and surgical risks. In July 1989, the first successful LRLTx was performed in an 11-month-old child, using a left lateral lobe of its mother [1]. In the beginning of the 1990s, LRLTx for adult recipients was performed by using left liver lobes in the same way including the middle hepatic vein (MHV) and later, with further experience, utilizing the right liver lobe (e.g. extended right lobe). With today s experience the right liver lobe is most commonly used for adults and liver segments II and III for paediatric recipients [2,3]. LRLTx was first developed and performed in Asia and the USA. At the beginning of the 1990s, LRLTx was introduced in Europe, initially only in larger centres (Great Britain, 1994; France, 1993; Spain, 1994; Belgium, 1993; Germany, 1991; etc.). As waiting time and pre-ltx mortality could be Nephrol Dial Transplant Vol. 19 Suppl 4 ß ERA EDTA 2004; all rights reserved

2 Living-donor liver transplantation European experiences significantly reduced for paediatric recipients by using split livers and LRLTx, the LRLTx became an established treatment modality for both adult and paediatric patients. Initially, the donor and the recipient operation tended to show higher morbidity. Blood loss was high and the graft function was not optimal. The venous drainage of the graft was often impaired and the incidence of biliary complications was high [4 7]. This was caused by technical problems and small liver graft volume. In order to overcome these problems, new methods of liver resection, such as dissection of the liver parenchyma without hilar occlusion (Pringle manoeuver), were developed, resulting in better graft function. To further optimize the donor operation, microsurgical techniques were used for reconstruction of vessels and bile ducts. This resulted in better outcome with less complications, i.e. reduction of vasculary and biliary complications in donors and recipients. The most extensive experiences with LRLTx were initially made in Asia. Over 2000 patients were transplanted with living donors. In the USA more than 300 LRLTx have been perfomed every year since In Europe, 46 of 118 registered transplant centres (data from ELTR) had already performed LRLTx in December Up to this time point more than 800 LRLTx were performed since In the years 2000 and 2001, a rapid increase in LTx of living donors, especially for adult recipients, was noticed. In Germany, over 11% of LTx are done by LRLTx (at centres in Berlin, Hannover, Essen, Hamburg, Mu nchen, Mainz, Heidelberg, Leipzig, Go ttingen and Jena). Current problems Medical discussions in the field of LRLTx include the need for high quality procedures, simplifying donor evaluation, optimizing surgical techniques and immunosuppression. Diagnostics Preoperative estimation of hepatic steatosis, exclusion of focal lesions, assessment of variations of the biliary, arterial and portal-venous tree in the donor using appropriate diagnostics is crucial. These diagnostics are being implemented by using intraoperative ultrasound and cholangiography (for donation of right lobe). Preoperative diagnostics The preoperative diagnostic evaluation resembles a multilevel evaluation process [3,8,9]. In this procedure not only the recipient compatibility, but also psychosomatic evaluation of the donor and the risk profile of the surgical procedure is evaluated, based on morphological and anatomical characteristics of the iv17 donor liver. Good experience has been made within the field of diagnostic imaging (e.g. CT scan, MRI, angiography). The aim is to characterize the donor liver completely by using only one noninvasive diagnostic method. On the one hand, morphological characteristics have to be described, volume and quality of liver (amount of steatosis, fibrotic changes, etc.), and, on the other hand, exclusion of lesions and, if present, description of their severity have to be made. For further surgical planning beforehand, clarification of vessel and biliary anatomy is most important [10]. Anatomical variations can change the surgical strategy and sometimes even exclude donors in rare cases (e.g. multiple portal vein branches of the right lobe for right lobe donation) [4]. To estimate the quality of the liver parenchyma, ultrasound and CT scan were introduced [6,7,9,11]. In some cases a fine needle liver biopsy has to be done to assess the exact measurement and quantification of donor liver steatosis. Potential complications have in some instances impeded a donation, so that the indication in unclear cases is not warranted in a healthy donor and is thereby seen as controversial. Variations of the liver artery and the portal branches have been visualized by the use of angiography (DSA) and biliary variations by endoscopic retrograde cholangiography (ERC). A three-dimensional visualization of the venous system could initially not be done. At present, with modern CT techniques and new MRI systems, this can be done [8,11]. ERC and DSA are invasive methods with the possibility of iatrogenous complications and for that reason should not be done if possible [12]. With the use of different MRI techniques and data processing within 30 min [8] it has become possible to show the liver quality and volume, and vessel and biliary anatomy by using one procedure [8]. The imaging systems have the capacity to demonstrate three-dimensional pictures. The calculated liver volume by imaging systems differed from intraoperatively measured liver volume by %. The venous imaging could be performed with absolute precision. In other studies, it could be shown that the MHV was captured in relation to the caval vein correctly in 93% of donors by MRI and in 84% by ultrasound. Good correlation was also seen when MRCP was compared to intraoperative cholangiography (in some centres the use of cholangiography is mandatory). The detection of accessory vessels in the perihepatic portal-venous [12] and arterial circuits is also shown to be sensitive with the use of noninvasive diagnostics. In many centres the modern MRI diagnostics present the standard imaging system for the donor evaluation and invasive imaging has only to be performed in unclear situations. Furthermore, MRI has been used more often for graft evaluation post-ltx. Another method to answer all relevant questions before LRLTx is being evaluated by the use of a multidetector CT scan [9]. By intravenous dye application, the imaging of biliary variations [9] (segment IV) could be enhanced. Compared to modern MRI diagnostics, three-dimensional imaging is possible [11].

3 Donor surgery The surgical outcome of the living-donor operation demands a great deal of preparation, minimizing the potential harm to the donor and gaining maximum graft quality. This requires meticulous attention to every detail in the donor and recipient operation. Because of the elective surgical procedure cold ischaemia time can be shortened. Careful preparation and blood sparing surgery can significantly lower the morbidity of LRLTx. Warm ischaemic time should be minimized, if not even completely, avoided. Resection of the liver for living donation is performed without hilar occlusion or only by using intermittent clamping [2,4]. After intraoperative imaging (ultrasound and cholangiography), the liver lobe is mobilized and dissection of the caval vein is performed. Bigger dorsal branches of hepatic veins (>5 mm in diameter) should be reanastomosed directly to the caval vein of the recipient for better venous drainage of the graft [7]. The arterial and portal venous structures are then dissected in the hepatoduodenal ligament. Dissection of the right hepatic artery begins right of the biliary duct in order to preserve small branches for the main duct [2]. The dissection of the biliary duct is performed at this time or during the resection of the liver parenchyma. In order to maintain the arterial supply of the duct, no electro-coagulation of the immediate periductal liver parenchyma should be done. Blood loss and corresponding blood supply by transfusion increases perioperative morbidity and mortality. This risk is not tampered by using autologous transfusions and especially for the donor operation, strategies to reduce blood loss had to be developed [3]. Furthermore, blood saving techniques have the advantage of creating a better overview and identification of important structures during resection of the liver. For technical performance either ultrasound dissection or waterjet dissection is being used. In our experience the use of bipolar electrocoagulation has also been shown to be effective for smaller vessels. To interact with diffuse bleeding, the use of infrarediv18 Intraoperative diagnostics In liver surgery, intraoperative ultrasound and cholangiography, cytological and histological measures for specifying the severity of liver lesions are established, so that technical and anatomical aspects for surgical decisions can be taken into account. In the surgical procedure of the donor, routine intraoperative ultrasound is done to localize the hepatic veins (e.g. MHV) [13]. Anatomical variations can be detected and localized with the use of intraoperative cholangiography. As a result of this, an immediate change in the surgical procedure can be performed [2,7]. Describing the course of the MHV, the plane of resection can be placed. Apart from visualizing hepatic veins and the caval vein, the portal vein anatomy and arterial supply of the liver can also be described exactly. Depending on the findings of cholangiography, the resection line for the biliary tree (one duct or more) can be assessed. Cholangiography is mainly done in living donors for the right liver lobe, as anatomical variations tend to be higher in these cases [7,14]. Throughout the recipient operation the old liver compared to early and late after reperfusion of the new liver portal vein, hepatic vein and arterial flow can be controlled. Using this possibility, a decrease or stop in blood flow by stenosis can be corrected immediately in situ [2,12]. Furthermore, compression of large donor organs in paediatric recipients by abdominal closure can be avoided [2]. Therefore, intraoperative ultrasound helps technical intraoperative problem solving. Indication and extended indication Clinical experience has shown that the willingness to donate increases in relatives the more advanced the condition of the potential organ donor becomes. As LRLTx amplifies the donor pool, extending the indication for this procedure is at present more often discussed. This option is being evaluated especially in patients with acute decompensation of chronic liver disease and advanced hepatocellular carcinoma (HCC), other primary liver tumours or non-resectable metastases of extrahepatic tumoural origin. Patients with acute and life-threatening complications would not receive a cadaver organ within a suitable time frame to make transplantation feasible. The outcome after LRLTx has been shown to be worse than in patients receiving a cadaver organ, most often triggered by infectious complications. Patients with a locally advanced HCC are per se not good candidates for conventional cadaver LTx. Retrospective studies have shown that by performing LTx in these tumour patients, acceptable long-term outcomes can be seen with a 50% 5 year survival. In patients with HCC diameters >5 cm, bilobular manifestations and microscopic vascular infiltration, this procedure requires further discussion. Surgical techniques U. Settmacher et al. The LRLTx is performed by surgeons who also have adequate experience in surgical oncology of the liver. The techniques used in the setting of LRLTx are primarily derived from liver resections used for surgical oncology and then modified to address problems in transplantation surgery, such as cold ischaemia time, vessel reconstruction, etc. The decision of which liver lobe to resect is based on the size and weight relations of the donor and recipient (inclusive body mass index, BMI) [3,6,7]. In general, the left lobe comprising segments II and III (Couinaud classification) is used for paediatric recipients and segments V VIII for adult recipients. In very few centres and in recipients weighing kg, the left liver lobe (segments II IV±I) is transplanted [3].

4 Living-donor liver transplantation European experiences coagulation is mandatory. By using these dissection techniques an optimal preparation of important structures, such as the MHV is possible. In this case, a long segment of the MHV can be prepared for the graft without resecting more liver parenchyma. The inclusion of a peripheral segment vs the inclusion of the entire MHV in the graft is still discussed [5]. Many authors tend to resect the MHV either for the right or left lobe graft in order to avoid venous compression of the medial segments due to venous outflow obstruction [7]. The venous drainage of the graft by the MHV after reperfusion seems to be functionally significant [5]. External drainage of the recipient biliary duct is performed by cystic duct or T-tube drainage in most cases [7,15]. Decompression relief on the biliary tree after surgery is shown to decrease the incidence for complications. After resection of the right lobe, in the postoperative period kinking between the main portal vein and the left portal vein is often present. This is enhanced by the postoperative hypertrophy of the remaining left lobe. In order to prevent kinking in the region of the portal vein and hepatic veins due to rotation of the remaining liver (mainly left lobe), the latter is fixed to the falciforme ligament before abdominal closure. Recipient surgery The recipient operation is performed without the use of veno-venous bypass. A complete clamping of the caval vein, if necessary, is performed only during a short period, so that the haemodynamic burden for the recipient is small. Profound discussion about the main hepatic vein and its anastomosing technique to the caval vein and the reconstruction of accessory hepatic veins, and especially, of the MHV, have yielded a variety of possibilities. For anastomosing the main hepatic vein, the right ostium or the ostium of the middle and left veins of the recipient is used and the opening of the caval vein enhanced by a longitudinal incision. For plastic reconstruction to the caval vein a higher number of variatons have been described in the field of full size and split-liver transplantation [3,6,16]. Compromised venous outflow of the splitliver graft has been one of the causes of early postoperative graft dysfunction. Many different options of plastic enhancement of the caval ostium for anastomosing the main hepatic vein of the graft were proposed to avoid this problem [7]. A main key in preventing graft congestion and in optimizing venous outflow, is the reconstruction and reimplantation of accessory dorsal hepatic veins and branches of the MHV. There is consensus to implant and reconstruct hepatic veins >5 mm in diameter to the caval vein directly or by various interpositions. At present the resection of the peripheral segment of the MHV and either direct implantation or by venous interposition grafts to the recipients caval vein remains accepted and widely practised. For this purpose native veins, iliac vein, femoral vein, saphenous vein of the recipient or iv19 the left portal vein branch of the explanted recipient organ, were used. The reconstruction of the portal vein is performed as an end-to-end anastomosis with running suture. Complex reconstructions have to be done in cases of anatomical variations or thrombosis of the portal vein region of the recipient. Most of the experience was gained from paediatric transplantation [6]. In these cases the portal vein shaft remained in the recipient and the so-called branch patch anastomosis was done in order to compensate for differences of vessel calibres. If thrombotic occlusion or malformation of the portal vein are present, either vessel interpositions [6] or partial or complete arterializations have to be done [17]. The iliac vein was used for interposition in paediatric recipients when the portal vein was hypoplastic. Alternatively, the mesenteric vein or the ovaric vein of the living donor was used. The use of cryoconserved veins often led to thrombotic occlusions [6]. If possible, no vessel interposition should be utilized for the arterial anastomosis [6,16]. Dependent on some anatomical problems, in some cases interpositions will have to be used, although this is not desirable. The outcome is mainly dependent on the type of interposition (material, fresh, cryoconserved), the inflow and outflow situation, and the surgical techniques. For arterial anastomosis we use vessel interpositions in 10% of patients [17]. There has been good experience utilizing inferior mesenteric vein and middle colic artery. The initial experience was made in children utilizing cryopreserved veins and the native great saphenous vein [6,17]. In these cases the reconstruction was performed at the back table with a second step, the reconstruction of the central anastomosis to the aorta [6]. Little experience has been gained with cryopreserved vessels used for interposition [16]. There remains an ongoing debate on when and how to do the type of reperfusion of the graft. Advantages and disadvantages of a very short warm ischaemic time with only portal or retrogradic reperfusion vs simultaneous (i.e. arterial and portal-venous) reperfusion vs only arterial reperfusion have been discussed. Based on our own experience, the simultaneous reperfusion technique can be recommended. Another interesting, but only superficially mentioned problem after split-liver transplantation, is the development of a so called hyper-perfusion syndrome. Not only after resection of a big liver volume, but also after resection of a critical small for size graft, may overflush the graft with too much perfusion volume, leading to difficult organ dysfunction. This is the case in patients with liver cirrhosis with already elevated arterial and portal flows. For this reason a decrease of portal-venous bloodflow can be achieved by central ligation of the lienal artery or by performing a partial portosystemic shunt. A major technical problem is caused by reconstruction of the biliary tree. The main reasons for early postoperative morbidity are biliary complications caused by extended resection with biliary reconstruction as seen in split-liver or full-size transplantation

5 iv20 [2,16,18]. Only small and short biliary ducts are at one s disposal for surgical reconstruction. Especially in the case of right lobe liver donation, numerous different anatomical variations are found and more than one duct has to be reconstructed. Surgeons should be cautious with biliary tree variation of segment I. The possibility of intraluminal stenting of these anastomoses is instructive for the surgical practice. Initially, in all recipients, a hepaticojejunostomy was performed based on the experience with paediatric transplantation. Nowadays, the use of a duct-to-duct anastomsis is favoured [6,18]. Using this technique, endoscopic intervention by ERC is easily feasible [6,18]. Drainage of the bile externally (by external bile duct drainages or T-tubes) is performed in many different ways [2]. In the case of more than one biliary ostium, the preferred way of anastomosing the biliary tree is by performing just one main biliary anastomosis [2]. In general, the narcotics used during LRLTx are similar to those used in LTx. While resecting the liver, the central-venous pressure should be as low as possible. Medical supplements to condition the graft, such as application of prostanoids or using Xenon narcotics, are used in clinical studies at this point. Immunosuppression There is no difference in the use of postoperative immunosuppression after LRLTx compared to conventional cadaver LTx. In our experience, minor dose changes are followed by a more sensible reaction during the induction phase. To what amount an immunological advantage is provided by living donation cannot be clearly addressed at this point. More clinical and experimental trials have to be performed. From a logistic standpoint LRLTx seems to be ideal for the induction of tolerance. Results The perioperative morbidity of the donor including all minor complications is stated to be 10 25% [3,7,15]. Biliary complications (5 10%) constitute a major portion (see Table 1). In the European experience, the donor mortality is shown to be % and is much lower than the mortality rate after liver resection for other purposes (Table 1). The results of LRLTx for paediatric and adult recipients are comparable. The perioperative complication rate is slightly higher in LRLTx than after cadaver transplantation. This can be explained by the complexity of the surgical intervention with more potential technical complications and the limited experiences so far. This can further be explained by more extended indications with higher incidence of tumour recurrence and infectious complications in these recipients. U. Settmacher et al. Table 1. Data in 25 European centres performing LRLTx (informal survey, March 2003) Concluding remarks In recent years LRLTx has emerged as a clinically safe alternative to cadaver transplantation in many cases and has further extended the donor pool. LRLTx has been shown to be a good option for patients with liver disease in which a long waiting time is not permitted. As an elective procedure, it allows the complex surgical aspects to be better planned. Extended indications for LRLTx remain to be discussed further. Conflict of interest statement. None declared. References Adults (n ¼ 408) Paediatric (n ¼ 499) Tumour indications 152 (37%) 21 (4.2%) One year survival 82% 78% re-ltx 30 (7.4%) 26 (54%) Biliary complications 110 (27%) 72 (14.4%) (recipient) Donor complications Total 124 (30.4%) 57 (11.4%) Biliary 35 (8.6%) 16 (3.2%) Mortality 3 (0.7%) 1 (0.2%) 1. Strong RW, Lynch SV, Ong TH, Matsunami H, Koido Y, Balderson GA. Successful liver transplantation from a living donor to her son. N Engl J Med 1990; 322: Fan ST, Lo CM, Liu CL, Wong J. Biliary reconstruction and complications of right lobe live donor liver transplantation. Ann Surg 2002; 236: Marcos A, Fisher RA, Ham JM et al. Right lobe living donor liver transplantation. 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6 Living-donor liver transplantation European experiences computed tomography in evaluating donors for adult living related liver transplants. Liver Transplant 2001; 7: Hagspiel KD, Leung DA, Angle JF et al. MR angiography of the mesenteric vasculature. Radiol Clin North Am 2002; 40: Huang TL, Cheng YF, Chen CL et al. Intraoperative Doppler ultrasound in living-related liver transplantation. Transplant Proc 2000; 32: Settmacher U, Steinmu ller T, Schmidt SC et al. Technique of bile duct reconstruction and management of biliary complications in right lobe living donor liver transplantation. Clin Transplant 2003; 17: iv Testa G, Malago M, Valentin-Gamazo C, Lindell G, Broelsch CE. Biliary anastomosis in living related liver transplantation using the right liver lobe: techniques and complications. Liver Transplant 2000; 6: Miller CM, Gondolesi GE, Florman S et al. One hundred and nine living donor liver transplants in adults and children: a single-center experience. Ann Surg 2001; 234: Settmacher U, Steinmu ller T, Luck W et al. Complex vascular reconstructions in living donor liver transplantation. Transplant Int 2003; 16: Schwarzenberg SJ, Sharp HL, Payne WD et al. Biliary stricture in living-related donor liver transplantation: management with balloon dilation. Pediatr Transplant 2002; 6: