Key words : Kidney transplant, Liver transplant, Transplant surgery

Introduction
Liver transplantation is the best treatment option for acute and chronic liver failure. Liver transplant initially started with deceased donors; however, because of insufficient numbers of deceased donors, living donor liver transplant (LDLT) was started. Appropriate donor selection for both of these transplant methods will increase the success of liver transplants. In addition, the correct determination of deceased donor criteria will increase the use of many unused and marginal donor livers.^1-3

The application of LDLT has several theoretical advantages for the recipient: transplant can be performed electively before serious decompensation occurs in the recipient, complications associated with organ preservation are minimized, and grafts of optimal quality are provided. Living donor liver transplant offers the possibility of liver replacement to selected patients who may be ineligible for deceased donor organ transplant.^4,5 The drawback of this technique is the potential risk of death or serious complications in donors and a greater incidence of technical complications in recipients.^6,7 Exhaustive medical and psychological evaluations and a precise anatomical study of the liver should be performed to guarantee the safety of the donor and to provide good results for the recipient.^3,8 To date, there is still no gold standard algorithm for the evaluation of the living candidate for liver donation. In this study, we evaluated the Baskent University deceased and living donor criteria. We retrospectively analyzed the data of candidates who were rejected.

Materials and Methods
Our team performed the first successful deceased donor liver transplant (DDLT) in the combined region of Turkey, the Middle East, and North Africa on December 8, 1988.9,10 On March 15, 1990, we succeeded with the first pediatric segmental LDLT in Turkey, the Middle and Near East, and Europe. On April 24, 1990, our team performed a left-lobe LDLT on an adult, which was the first in the world.^1,11 On May 16, 1992, our team performed a combined liver-kidney transplant from a living related donor, which was the first operation of its kind anywhere in the world.¹² Since 1988, we have performed 704 liver transplants (490 LDLT [69.6%] and 214 DDLT [30.4%]) at our 3 transplant centers (Ankara, Adana, Istanbul). During this period, 1387 candidates for living donation were evaluated at our center, and 938 were rejected (67.6%).

Baskent University living donor evaluation criteria
The policy of our program is to present the possibility of LDLT to all potential recipients at the time of evaluation for liver transplant. The most important evaluation criterion for donors is the relationship between the donor and recipient; accordingly, the candidates must be relatives of the recipient (up to the 4th degree) or the spouse of the recipient, and candidates must be ?18 years old. Candidates who meet these criteria are considered for medical evaluation.

The protocol for candidate evaluation is designed in stages so that testing proceeds from simple and noninvasive tests to more complex and invasive tests, including liver biopsy (Table 1). The first interview with the donor candidate is always performed by a transplant surgeon. This interview is important to inform the candidate about the details of the surgery, postoperative care, complications, and reported outcomes associated with donation. During the interview, morbidity and mortality risks are thoroughly discussed with the candidate. Next, the candidate undergoes evaluation of a complete medical history and a physical examination. In the first evaluation, if the donor’s body mass index (BMI; as the ratio of the patient’s weight in kilograms divided by the squared value of height in meters) is higher than 35, then the donor is rejected. The blood group identity is an important condition. Candidates are rejected if they have abnormal liver function tests, positive serology for acute hepatitis A and/or hepatitis C, and/or positive core antibody for hepatitis B. Potential candidates then undergo abdominal ultrasonography, chest radiography, and electrocardiography.

In the second step, we perform triphasic abdominal computed tomography (CT) to assess the arterial and venous anatomy, to estimate the volume of total and remnant liver, and to detect any abnormalities. If graft-to-recipient weight ratio is >1 and the remnant liver volume is ?40% of the total liver volume, then the candidate is accepted for further evaluation. If the remnant liver volume is <40%, then the candidate is rejected. Candidates with CT findings such as hepatic calcification, severe hepatic steatosis, hydatid cyst, biliary dilatation, or any malignancy are rejected.

In the third step, general operative risk assessment is performed, including pulmonary function test, echocardiography, and stress test. After these tests, cardiologists and pulmonologists evaluate the candidates. Members from the departments of cardiology, pulmonology, hepatology, and psychiatry routinely evaluate the patient; if necessary, other department consultations may be requested.

Step 4 includes a magnetic resonance cholangiography scan to evaluate the bile anatomy (since October 2006). In the final (fifth) step, if the first 4 steps are normal, we always perform liver biopsy. We prefer ultrasonography-guided liver biopsy. Specimens are obtained separately from the right lobe and left lobe with an 18-gauge biopsy needle (at least 10 different portal triads for each specimen). All liver biopsy specimens are fixed in formalin and embedded in paraffin. Biopsies are prepared with hematoxylin and eosin, Masson trichrome, and Gomori reticulin stains to identify collagen fibers and with Perls stain, which reveals iron. An experienced pathologist evaluates all biopsy specimens. After histopathological examination, candidates are rejected if they have chronic hepatitis, cirrhosis, severe hepatocellular injury, diffuse hepatocellular ballooning, or moderate-to-severe macrovesicular fatty changes over 20%.

Baskent University deceased donor evaluation criteria
For all deceased donors, biochemical evaluations should be normal, and there should be no known liver diseases and no acute active infection. During procurement, we perform liver biopsy and frozen-section examination for all deceased donors. After histopathological examination, if we confirm chronic hepatitis, cirrhosis, severe hepatocellular injury, moderate diffuse hepatocellular ballooning, and severe macrovesicular fatty changes >20%, the candidate is rejected. Refusal criteria for the deceased donor include hypernatremia, sepsis, extra cranial malignancy, and high-dose vasopressor support.

Recipient surgical procedures
At our institution, liver transplants are performed according to techniques that have been described previously.^9,10 The partial liver graft is perfused with University of Wisconsin solution through the portal vein, the hepatic artery, and the hepatic duct. In the recipient, the diseased liver is removed, leaving the inferior vena cava intact with the right hepatic vein and the trunk of the middle hepatic vein and left hepatic vein clamped separately. For LDLT procedures, we perform the hepatic vein anastomoses, depending on the graft’s vein side. When the right liver lobe is transplanted, we perform hepatic anastomoses to the recipient’s right hepatic vein conduit. When the graft is either a left lobe or a left lateral lobe, we close the right hepatic vein conduit and perform the anastomosis after a venoplasty of the middle-left vein conduit of the recipient. In some cases, especially with DDLT, we close both sides of the vena cava conduit of the graft. We then perform a side-to-side vena cava anastomosis. Reconstruction of the portal vein is performed using an end-to-end venovenous anastomosis. The graft’s hepatic artery is anastomosed to the hepatic artery of the recipient. Our first choice for biliary reconstruction is duct-to-duct anastomosis. If the recipient’s biliary tract is thin or if the liver is affecting the biliary tract, such as sclerosing cholangitis or cholangiocellular carcinoma, then we prefer Roux-en-Y hepaticojejunostomy.

Results
In our review of liver transplant candidates from March 1990 to January 2020, 449 potential donors (32.3%) were considered as suitable for donation and 938 potential donors (67.7%) were rejected. There were 208 men (46.3%) and 241 women (53.7%) who had donor hepatectomy, with mean age of 34.8 ± 8.8 years (range, 25-65 years). All donors were related (379 were relatives [84.4%] of the recipients, and 70 were spouses [15.6%] of the recipients). In the rejected group of donor candidates, there were 539 men (57.4%) and 399 women (42.6%), with mean age of 36.3 ± 18.4 years (range, 18-65 years). All rejected donor candidates were related (820 were relatives [87.4%] of the recipients, and 118 were spouses [12.6%] of the recipients).

There were 218 candidates (23.2%) who were rejected after physical and psychosocial evaluation (step 1), 439 candidates (46.8%) were rejected after evaluation with CT angiography (step 2), 57 candidates (6%) were rejected after assessment of the general operative risk (step 3), and 224 candidates (23.8%) were rejected because of abnormal pathological findings (step 5). Donor rejection was not evaluated on the basis of magnetic resonance cholangiography (step 4).

When we considered step 1, we noted that 96 donor candidates chose not to donate (anxiety as the reason) after they received information about liver surgery and the postoperative course. There were 18 candidates who were rejected because of medical comorbidity such as diabetes mellitus, hypertension, and coronary vascular disease. Also, 45 candidates had BMI values that were higher than 35. Blood group mismatch was detected in 21 candidates. There were 25 candidates who had abnormal laboratory findings (12 candidates with hyperlipidemia, 7 with hepatitis B surface antigen positive, 5 with elevated liver function tests, and 1 with anemia). When we performed abdominal ultrasonography, we discovered severe hepatic steatosis in 13 candidates.

In step 2, we used CT angiography to evaluate all donor candidates who had no issues shown during step 1. We rejected 392 candidates because of inadequate volume and/or vascular anomalies. In 47 patients, we detected abnormal CT findings (17 patients with serious hepatic steatosis, 7 with hemangioma, 3 with liver cyst hydatid, 2 with hepatic calcification, 2 with biliary tract cystic dilatation, 2 with diffuse splenomegaly, 1 with multiple liver cyst, 1 with focal nodular hyperplasia, and 12 others unspecified here).

In step 3, the other departments (cardiology, pulmonology, hepatology, psychiatry, and, if necessary, other departments) evaluated the candidates. There were 38 donors (2.7%) who were rejected because of medical comorbidities diagnosed during evaluation (7 donors with coronary vascular disease, 5 with chronic obstructive lung disease, 3 with diabetes mellitus, 2 with pancreas adenocarcinoma, 1 with hypertension, 1 with severe factor 7 deficiency, 1 with tuberculosis, 1 with multiple sclerosis, 1 with Crohn disease, 1 with ovarian carcinoma, 1 with renal cell carcinoma, 1 with thyroid papillary carcinoma, 1 with osteosarcoma, and 12 others). Also, 19 candidates were rejected after the detection of previously unknown psychiatric diseases.

In step 4, we did not reject any candidate. In fact, we have performed magnetic resonance cholangiography for assessment of biliary tract rather than for use as a tool for elimination. In step 5, we rejected 224 candidates: 177 candidates with moderate-to-severe macrovesicular fatty changes (between 30% and 90%), 22 with severe hepatocellular injury, 11 with chronic hepatitis, 6 with diffuse hepatocellular ballooning, 3 with early cirrhosis, 3 with biliary cholangitis, and 1 with iron deposits on liver.

We also evaluated the early postoperative donor hepatectomy complications. Donor complications were divided into 3 groups: mild, moderate, and severe. Overall, 398 of 449 donors (88.7%) had no complications. Postoperative complications occurred in 51 patients (11.3%). There were 31 donors (6.9%) who developed minor complications that did not require any intervention, and these were named as mild complications. The following mild complications were observed: intra-abdominal hematoma (n = 4), ileus (n = 3), incisional infection (n = 3), pulmonary atelectasis (n = 3), fluid/electrolyte problems (n = 2), neuropraxia of arm (n = 2), hypoalbuminemia (n = 3), pulmonary embolism (n = 3), deep vein thrombosis (n = 3), pneumonia (n = 3), and anemia requiring blood transfusion (n = 2). Moderate complications occurred in 19 donors (4.2%); these included intra-abdominal collection (n = 7), biliary leak (n = 6), pleural effusion (n = 3), intra-abdominal bleeding (n = 1), intestinal perforation (n = 1), and deep surgical site infection (n = 1). All intra-abdominal collections were treated with interventional radiological techniques.

In 5 patients, we placed drainage catheters. The catheters were removed when the amount of fluid received was below 30 mL/day. The average removal time of the catheters was 7.8 ± 3.3 days after catheter insertion. In 2 patients, collections were treated with ultrasonography-guided percutaneous aspiration. In 6 donors, percutaneous drainage catheters were inserted to mitigate biliary leaks. In 5 patients, biliary leaks ended spontaneously 10.4 ± 2 days after catheter insertion. Only 1 patient with biliary leakage received endoscopic retrograde cholangiopancreatography. All of the pleural effusions (n = 3) were treated with ultrasonography-guided percutaneous aspiration.

Only 3 patients required reoperation, to mitigate bleeding, perforation, and deep surgical side infection. There was only 1 severe complication: organ failure caused by unspecified liver necrosis. In this case, the patient’s liver enzymes increased on day 7 after transplant. Although major vascular structures were normal in triphasic abdominal CT angiography, extensive necrosis was observed in the remnant liver. Also, we performed ultrasonography-guided liver biopsy, which revealed necrosis. Plasmapheresis was applied as a conservative treatment, and emergency DDLT was done. Liver transplant was performed from the deceased donor within 48 hours after diagnosis. The patient with the severe complication died on day 15 after transplant as a result of pulmonary complications.

Discussion
Since the first successful LDLT in 1990, LDLT has been a good choice for patients with chronic liver failure. As a result of the increasing number of patients with chronic liver failure in the world and lack of deceased donor organ donation in many countries, the number of LDLT procedures has been increasing.^2,13 For the recipient, LDLT has 3 advantages over DDLT. First, wait time for LDLT is shorter than for DDLT. Second, an organ from a living donor may have better quality than an organ from a deceased donor because most living donors undergo extensive testing that is not done for deceased donors. Third, cold ischemia time is markedly shorter in LDLT.^4,5,14 The selected donor candidate must be carefully evaluated before LDLT. A thorough evaluation of the living donor candidate is guided by 2 objectives: the first is to ensure the safety of the surgical procedure for the donor, and the second is to identify donor grafts that pose potential risks for the recipient. Therefore, the ideal evaluation process should thoroughly assess potential graft function while minimizing risks to the donor candidate. This is best achieved by an exhaustive medical and psychological evaluation of the donor, as well as a precise study of the size, anatomy, and quality of the liver graft.^3,15,16

During the evaluation process, we observed that approximately 60% of the potential donors had abnormalities that prevented donation.¹⁶ Living donor liver transplant is not a complication-free procedure for donors. Psychosocial assessment is one of the most important steps in donor evaluation. The donor must be informed of the typical risks of the operation and the possibility of mortality during and after the procedure.³ In the literature, donor rejection rates of between 2% and 20% have been reported after psychosocial evaluation.^16-20 In our series, 96 donor candidates (6.9%) chose not to donate after being informed about liver surgery, morbidity, and mortality. We believe that an important aspect of the evaluation is the establishment of a process of fully informed consent to protect the donor. Any potential living donor candidate should be well-informed about the risks of the surgery, and highly dedicated donors should be chosen.

The preoperative radiological imaging is aimed at establishing the quality of the potential liver graft and to facilitate safe procurement of the graft from donors. Preoperative radiological imaging includes assessment of hepatic vascular anatomy, biliary anatomy, liver volume, and hepatic parenchyma.^21-23 The evaluation of the remnant liver and graft volume is an important aspect in the process of donor selection.^16,24 Volumetric measurements assessed with triphasic CT or magnetic resonance imaging yield equally satisfactory results for calculating the graft and remnant liver volume.²³

The success of LDLT depends on the provision of adequate graft volume. The graft-to-recipient weight ratio or the ratio of graft volume to estimated standard liver volume of the recipient is a method for determination of the ideal liver volume for recipients. The size and type of liver graft obtained are based on an adequate graft-to-recipient weight ratio or the ratio of graft volume to estimated standard liver volume of the recipient, and a minimum of 1% or 40%, respectively, is acceptable.^24,25 Inomata and colleagues reported that the survival rate of a recipient with a graft-to-recipient weight ratio of less than 0.8% was worse than the survival rate of recipients with a ratio of 0.8% to 1%.²⁶ Lo and colleagues reported a 95% survival rate with a graft volume that exceeded 40% of estimated standard liver volume versus a 40% survival rate with graft volume less than 40%.27 When the estimated liver residual volume is less than 40%, the candidate should not be considered eligible as a living donor.^16,24 In the literature, there are reports that safe transplant is achieved if the remaining liver volume exceeds 30% of the total volume.²⁸ We prefer to transplant a graft with a graft-to-recipient weight ratio greater than 1%, and we do not prefer remnant liver volume less than 40%. In our patients, preoperatively calculated graft volumes were precisely similar to the graft weight on the back table, and none of the donors experienced hepatic insufficiency caused by insufficient liver volume after hepatectomy.

One unresolved issue in the LDLT evaluation process is the need for liver biopsies. A survey of 42 transplant centers that perform LDLT showed that only 14% performed routine liver biopsies, 60% performed liver biopsies only in selected cases, and 26% did not perform biopsy in any donor candidates.²⁹ Ryan and colleagues reported no complications in 100 consecutive donors after percutaneous transhepatic biopsy.³⁰ Clinical, imaging, and biochemical parameters do not seem to be sufficiently accurate to judge the extent of some hepatic damage, especially hepatic steatosis. Livers with significant steatosis may increase the incidence of ischemia-reperfusion injury and primary nonfunction in the recipients.^31,32 Each 1% increase of steatosis might reduce the functional mass of the graft by 1%.³³ In addition, these biopsies provide valuable baseline/control materials to detect the accuracy of normal ranges of liver injury tests as a way to monitor hepatic injury. This source of control liver tissue is superior to any other source. Biopsy findings alone can contribute to donor exclusion.³⁴ Preoperative donor liver biopsy is a mandatory part of our donor evaluation protocol, and in our patient reported here we did not observe any complications due to liver biopsy. In our experience, although the results of laboratory and imaging studies (including CT) were normal, liver biopsy revealed an abnormal liver in 224 donors (16.1%). These abnormalities included chronic hepatitis, moderate and severe fatty changes, fibrosis, and severe hepatocellular injury. For our donor candidates, we only accepted donors with normal results on liver biopsy or those with no more than a mild degree of hepatic steatosis.

Despite careful selection of donors, it has been shown in the literature that donor morbidity and mortality may develop.^29,35,36 Multicenter studies in the literature have shown that 38% of living liver donors developed complications, with a mortality rate of about 0.2%.^37,38 Liver insufficiency is the main cause of donor mortality after donor hepatectomy.²⁹ We think that preoperative measurement of the future liver remnant combined with preoperative estimation of liver quality, especially the fatty degree, is a key point of investigation before donation. In accordance with our evaluation criteria, the residual liver volume must be ?40% of the total liver volume, and liver biopsy should be normal. As a result of the donor selection criteria that we applied, liver failure due to small remnant volume did not develop in our donors. However, 1 patient died of organ failure due to unspecified liver necrosis.

In the literature, biliary complications have been reported as the most common surgical complication after donor hepatectomy,^39,40 and it is said that biliary complications are associated with donor mortality.⁴¹ Despite advances in surgical technique, biliary tract complications after donor hepatectomy range from 1.9% to 14% with a median incidence of 5.8%.⁴² In some series published from the United States, Seoul (Korea), and Europe, the incidence of biliary complications was 6%, 7%, and 8%, respectively.^29,35,43 In our transplant center, we experienced 6 biliary complications (1.3%) after donor hepatectomy. We inserted a drainage catheter into biliary collections in 5 donors, and the leaks ended spontaneously after at most 3 weeks. In 1 patient, we managed the leak with endoscopic retrograde cholangiopancreatography.

Lung complications can also add to morbidity and mortality.⁴⁴ A history of smoking and the presence of obesity are important factors for the development of pulmonary complications.²⁰ We have had no mortality due to pulmonary complications, but we observed patients with pulmonary complications such as pulmonary atelectasis (n = 3), pulmonary embolism (n = 3), pneumonia (n = 3), and pleural effusion (n = 3). After these experiences, we accept only donors who abstain from smoking for a minimum of 6 weeks before the operation. In addition, since the beginning of our LDLT program, we do not accept living donors with a BMI ?35.

Conclusions
Organ procurement for liver transplant can be from deceased donors or living donors (related or paired exchange). According to our criteria, a living donor candidate must be a relative of the recipient (up to the 4th degree) or the spouse of the recipient (also for paired exchange transplant couples). Because the LDLT is not a complication-free procedure for donors, the first option for liver transplant should always be a DDLT. However, LDLT is a life-saving option, especially in acute liver failure and for cases in which the supply of deceased organs is inadequate. Donor safety should be the primary focus in LDLT. We believe that all potential living donor candidates should be well-informed about the risks of the surgery, and highly dedicated donors should be chosen. Living donor liver transplants should be performed only at well-established centers with surgical teams who have appropriate medical expertise and with adequate institutional resources. To reduce complications and provide adequately functional grafts, careful donor evaluation is imperative.

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