Eberhard L. Renner

A graft to body weight ratio less than 0.8 does not exclude adult‐to‐adult right‐lobe living donor liver transplantation

Many centers require a minimal graft to body weight ratio (GBWR) ≥ 0.8 as an arbitrary threshold to proceed with right‐lobe living donor liver transplantation (RL‐LDLT), and there is often hesitancy about transplanting lower volume living donor (LD) liver grafts into sicker patients. The data supporting this dogma, based on the early experience with RL‐LDLT at Asian centers, are weak. To determine the effect of LD liver volume in the modern era, we investigated the impact of GBWR on the outcome of RL‐LDLT with a GBWR as low as 0.6 at the University of Toronto. Between April 2000 and September 2008, 271 adult‐to‐adult RL‐LDLT procedures and 614 deceased donor liver transplants were performed. Twenty‐two living donor liver transplantation (LDLT) cases with a GBWR of 0.59 to 0.79 (group A) were compared with 249 LDLT cases with a GBWR ≥ 0.8 (group B) and with 66 full‐graft deceased donor liver transplants (group C), who were matched 3:1 according to donor and recipient age, Model for End‐Stage Liver Disease score, and presence of hepatitis C and hepatocellular carcinoma with the low‐GBWR group. Portal vein shunts were not used. Markers of reperfusion injury [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], graft function (international normalized ratio and bilirubin), complications graded by the Clavien score, and graft and patient survival were compared. As expected, LD recipients had a significantly shorter cold ischemia time (94 ± 43 minutes for A, 96 ± 57 minutes for B, and 453 ± 152 minutes for C, P = 0.0001). However, the peak AST, peak ALT, absolute decrease in the international normalized ratio, day 7 bilirubin level, postoperative creatinine clearance, complication rate graded by the Clavien score, and median hospital stay were similar in all groups. The rate of biliary complications was higher with LD grafts than deceased donor grafts (19% for A versus 10% for B and 0% for C, P = 0.2). Patient survival was similar in all groups at 1, 3, and 5 years (91% for A versus 89% for B and 93% for C at 1 year, 87% for A versus 81% for B and 89% for C at 3 years, and 83% for A versus 81% for B and 87% for C at 5 years, P = 0.63). A Cox proportional regression analysis revealed only hepatitis C virus as a risk factor for poorer graft survival and not GBWR as a continuous or categorical variable. In conclusion, we found no evidence of inferior outcomes with smaller size grafts versus larger size LD grafts or full‐size deceased donor grafts. Further studies are warranted to examine the factors affecting the function of smaller grafts for living liver donation and thereby define the safe lower limits for transplantation. Liver Transpl 15:1776–1782, 2009.

Radiotherapy as a bridge to liver transplantation for hepatocellular carcinoma

About 20% of the patients with advanced hepatocellular carcinoma (HCC) who are listed for liver transplantation (LT) are eventually delisted as a result of local tumor progression. Herein, we report our experience with conformal radiotherapy (CRT) as a novel bridge to LT. From July 2006 to August 2008, CRT was delivered in five or six fractions to patients with HCC listed for LT in whom either prior local therapies had failed or those not suitable for standard local therapies because of poor liver function or anatomic issues. Radiotherapy (RT) volumes and doses were individualized to spare the uninvolved liver with the goal of stabilizing the most aggressive HCC(s) in an attempt to reduce the chance of delisting as a result of tumor progression. Ten patients with tumor diameters ranging from 25 to 108 mm were treated. Eight out of 10 tumors were beyond Milan criteria. The median age was 55 (range 36–64). Seventy percent of the patients were male subjects. The median medical MELD score was 11 (range 9–17). The median irradiated HCC volume was 79 cc (range 15–798 cc). The median RT delivered dose was 33 Gy (range 8.5–54 Gy), in one to six fractions. The median dose to the uninvolved liver was 13.3 Gy (range 1.8–16.5). Nine patients completed their CRT as planned and one patient was transplanted after the first fraction. The treatment was well tolerated: Grade 1 nausea was reported in three patients, the platelet count decreased from 154 to 98 in one patient, and there were no other complications. No treated tumors progressed during or after the treatment. Two tumors remained stable; the rest had 10–50% regression, which was sustained on follow‐up imaging.  The median follow up was 14 months (range 3–20). Local tumor control was achieved in all treated tumors.Two patients were delisted as a result of cancer progression outside the treated field (one in the context of systemic metastases; yet another with progression of other untreated HCC in the liver). Three patients are still waiting for transplantation. Five patients underwent LT with no complications attributable to the CRT. Explant pathology, available for five patients, showed tumor necrosis and fibrosis with sparing of the untreated parenchyma. All transplanted patients treated with CRT are cancer‐free. CRT is a safe and efficacious local bridging therapy for patients with advanced HCC who are on the waiting list for LT. Further studies are warranted to compare the effectiveness of CRT to other local treatment regimens for HCC.

Recipient age affects long-term outcome and hepatitis C recurrence in old donor livers following transplantation.

We studied the role of donor and recipient age in transplantation/ischemia‐reperfusion injury (TIRI) and short‐ and long‐term graft and patient survival. Eight hundred twenty‐two patients underwent deceased donor liver transplantation, with 197 donors being ≥60 years old. We evaluated markers of reperfusion injury, graft function, and clinical outcomes as well as short‐ and long‐term graft and patient survival. Increased donor age was associated with more severe TIRI and decreased 3‐ and 5‐year graft survival (73% versus 85% and 72% versus 81%, P < 0.001) and patient survival (77% versus 88% and 77% versus 82%, P < 0.003). Hepatitis C virus (HCV) infection and recipient age were the only independent risk factors for graft and patient survival in patients receiving an older graft. In the HCV(+) cohort (297 patients), patients ≥ 50 years old who were transplanted with an older graft versus a younger graft had significantly decreased 3‐ and 5‐year graft survival (68% versus 83% and 64% versus 83%, P < 0.009). In contrast, HCV(+) patients < 50 years old had similar 3‐ and 5‐year graft survival if transplanted with either a young graft or an old graft (81% versus 82% and 81% versus 82%, P = 0.9). In conclusion, recipient age and HCV status affect the graft and patient survival of older livers. Combining older grafts with older recipients should be avoided, particularly in HCV(+) patients, whereas the effects of donor age can be minimized in younger recipients. Liver Transpl 15:1288–1295, 2009.

Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation: First North American results.

The European trial investigating normothermic ex vivo liver perfusion (NEVLP) as a preservation technique for liver transplantation (LT) uses gelofusine, a non–US Food and Drug Administration–approved, bovine‐derived, gelatin‐based perfusion solution. We report a safety and feasibility clinical NEVLP trial with human albumin–based Steen solution. Transplant outcomes of 10 human liver grafts that were perfused on the Metra device at 37 °C with Steen solution, plus 3 units of erythrocytes were compared with a matched historical control group of 30 grafts using cold storage (CS) as the preservation technique. Ten liver grafts were perfused for 480 minutes (340‐580 minutes). All livers cleared lactate (final lactate 1.46 mmol/L; 0.56‐1.74 mmol/L) and produced bile (61 mL; 14‐146 mL) during perfusion. No technical problems occurred during perfusion, and all NEVLP‐preserved grafts functioned well after LT. NEVLP versus CS had lower aspartate aminotransferase and alanine aminotransferase values on postoperative days 1‐3 without reaching significance. No difference in postoperative graft function between NEVLP and CS grafts was detected as measured by day 7 international normalized ratio (1.1 [1‐1.56] versus 1.1 [1‐1.3]; P = 0.5) and bilirubin (1.5; 1‐7.7 mg/dL versus 2.78; 0.4‐15 mg/dL; P = 0.5). No difference was found in the duration of intensive care unit stay (median, 1 versus 2 days; range, 0‐8 versus 0‐23 days; P = 0.5) and posttransplant hospital stay (median, 11 versus 13 days; range, 8‐17 versus 7‐89 days; P = 0.23). Major complications (Dindo‐Clavien ≥ 3b) occurred in 1 patient in the NEVLP group (10%) compared with 7 (23%) patients in the CS group (P = 0.5). No graft loss or patient death was observed in either group. Liver preservation with normothermic ex vivo perfusion with the Metra device using Steen solution is safe and results in comparable outcomes to CS after LT. Using US Food and Drug Administration–approved Steen solution will avoid a potential regulatory barrier in North America. Liver Transplantation 22 1501–1508 2016 AASLD.

Liver transplantation in patients with end-stage liver disease requiring intensive care unit admission and intubation

Data regarding transplantation outcomes in ventilated intensive care unit (ICU)–dependent patients with end‐stage liver disease (ESLD) are conflicting. This single‐center cohort study investigated the outcomes of patients with ESLD who were intubated with mechanical support before liver transplantation (LT). The ICU plus intubation group consisted of 42 patients with decompensated cirrhosis and mechanical ventilation before transplantation. LT was considered for intubated ICU patients if the fraction of inspired oxygen was ≤40% with a positive end‐expiratory pressure ≤ 10, low pressor requirements, and the absence of an active infection. Intubated ICU patients were compared to 80 patients requiring ICU admission before transplantation without intubation and to 126 matched non–ICU‐bound patients. Patients requiring ICU care with intubation and ICU care alone had more severe postoperative complications than non–ICU‐bound patients. Intubation before transplantation was associated with more postoperative pneumonias (15% in intubated ICU transplant candidates, 5% in ICU‐bound but not intubated patients, and 3% in control group patients; P = 0.02). Parameters of reperfusion injury and renal function on postoperative day (POD) 2 and POD 7 were similar in all groups. Bilirubin levels were higher in the ICU plus intubation group at POD 2 and POD 7 after transplantation but were normalized in all groups within 3 months. The ICU plus intubation group versus the ICU‐only group and the non‐ICU group had decreased 1‐, 3‐, and 5‐year graft survival (81% versus 84% versus 92%, 76% versus 78% versus 87%, and 71% versus 77% versus 84%, respectively; P = 0.19), but statistical significance was not reached. A Glasgow coma scale score of <7 versus >7 before transplantation was associated with high postoperative mortality in ICU‐bound patients requiring intubation (38% versus 23%; P = 0.01). In conclusion, ICU admission and mechanical ventilation should not be considered contraindications for LT. With careful patient selection, acceptable long‐term outcomes can be achieved despite increased postoperative complications. Liver Transpl 21:761–767, 2015.

Living vs. deceased donor liver transplantation provides comparable recovery of renal function in patients with hepatorenal syndrome: a matched case-control study.

Outcomes of living versus deceased donor liver transplantation in patients with chronic liver disease and hepatorenal syndrome (HRS) was compared using a matched pair study design. Thirty patients with HRS receiving a live donor liver transplantation (LDLT) and 90 HRS patients receiving a full graft deceased donor liver transplantation (DDLT) were compared. LDLT versus DDLT of patients with HRS was associated with decreased peak aspartate aminotransferase levels (339 ± 214 vs. 935 ± 1253 U/L; p = 0.0001), and similar 7‐day bilirubin (8.42 ± 7.89 vs. 6.95 ± 7.13 mg/dL; p = 0.35), and international normalized ratio levels (1.93 ± 0.62 vs. 1.78 ± 0.78; p = 0.314). LDLT vs. DDLT had a decreased intensive care unit (2 [1–39] vs. 4 [0–93] days; p = 0.004), and hospital stay (17 [4–313] vs. 26 [0–126] days; p = 0.016) and a similar incidence of overall postoperative complications (20% vs. 27%; p = 0.62). No difference was detected between LDLT and DDLT patients regarding graft survival at 1 (80% vs. 82%), at 3 (69% vs. 76%) and 5 years (65% vs. 76%) (p = 0.63), as well as patient survival at 1 (83% vs. 82%), 3 (72% vs. 77%) and 5 years (72% vs. 77%) (p = 0.93). The incidence of chronic kidney disease post‐LT (10% vs. 6%; p = 0.4) was similar between both groups. LDLT results in identical long‐term outcome when compared with DDLT in patients with HRS.

Live Donor Liver Transplantation: A Valid Alternative for Critically Ill Patients Suffering From Acute Liver Failure

We report the outcome of live donor liver transplantation (LDLT) for patients suffering from acute liver failure (ALF). From 2006 to 2013, all patients with ALF who received a LDLT (n = 7) at our institution were compared to all ALF patients receiving a deceased donor liver transplantation (DDLT = 26). Groups were comparable regarding pretransplant ICU stay (DDLT: 1 [0–7] vs. LDLT: 1 days [0–10]; p = 0.38), mechanical ventilation support (DDLT: 69% vs. LDLT: 57%; p = 0.66), inotropic drug requirement (DDLT: 27% vs. LDLT: 43%; p = 0.64) and dialysis (DDLT: 2 vs. LDLT: 0 patients; p = 1). Median evaluation time for live donors was 24 h (18–72 h). LDLT versus DDLT had similar incidence of overall postoperative complications (31% vs. 43%; p = 0.66). No difference was detected between LDLT and DDLT patients regarding 1‐ (DDLT: 92% vs. LDLT: 86%), 3‐ (DDLT: 92% vs. LDLT: 86%), and 5‐ (DDLT: 92% vs. LDLT: 86%) year graft and patient survival (p = 0.63). No severe donor complication (Dindo–Clavien ≥3 b) occurred after live liver donation. ALF is a severe disease with high mortality on liver transplant waiting lists worldwide. Therefore, LDLT is an attractive option since live donor work‐up can be expedited and liver transplantation can be performed within 24 h with excellent short‐ and long‐term outcomes.

Routine induction therapy in living donor liver transplantation prevents rejection but may promote recurrence of hepatitis C.

BACKGROUND Routine induction therapy in living donor liver transplantation (LDLT) has not been well described. METHODS We reviewed outcomes of induction therapy with rabbit antithymocyte globulin (rATG) or basiliximab within 1 year of LDLT. RESULTS Between 2002 and 2007, 184 adults underwent LDLT and received induction therapy in addition to standard immunosuppression. Acute cellular rejection (ACR) developed in 17 of 130 patients (13.1%) who received rATG and 13 of 54 patients (24.1%) who received basiliximab (P = .066). The interval between transplantation and rejection as well as rejection severity was similar in patients who received rATG and those who received basiliximab. Hepatitis C (HCV) recurrence requiring initiation of antiviral therapy was more common in patients who received rATG compared with basiliximab (34.5% vs 8.7%; P = .021), and in those who received induction combined with tacrolimus as opposed to cyclosporine (38.5% vs 3.9%; P = .001). rATG and basiliximab were associated with excellent patient and graft survivals well as low rates of opportunistic infections and malignancies. CONCLUSION Induction with rATG or basiliximab was well tolerated and highly effective at preventing ACR within 1 year of LDLT, but may be associated with a higher risk of clinically significant HCV recurrence in some patients.

Donor BMI >30 Is Not a Contraindication for Live Liver Donation

The increased prevalence of obesity worldwide threatens the pool of living liver donors. Although the negative effects of graft steatosis on liver donation and transplantation are well known, the impact of obesity in the absence of hepatic steatosis on outcome of living donor liver transplantation (LDLT) is unknown. Consequently, we compared the outcome of LDLT using donors with BMI <30 versus donors with BMI ≥30. Between April 2000 and May 2014, 105 patients received a right‐lobe liver graft from donors with BMI ≥30, whereas 364 recipients were transplanted with grafts from donors with BMI <30. Liver steatosis >10% was excluded in all donors with BMI >30 by imaging and liver biopsies. None of the donors had any other comorbidity. Donors with BMI <30 versus ≥30 had similar postoperative complication rates (Dindo‐Clavien ≥3b: 2% vs. 3%; p = 0.71) and lengths of hospital stay (6 vs. 6 days; p = 0.13). Recipient graft function, assessed by posttransplant peak serum bilirubin and international normalized ratio was identical. Furthermore, no difference was observed in recipient complication rates (Dindo‐Clavien ≥3b: 25% vs. 20%; p = 0.3) or lengths of hospital stay between groups. We concluded that donors with BMI ≥30, in the absence of graft steatosis, are not contraindicated for LDLT.

First‐Degree Living‐Related Donor Liver Transplantation in Autoimmune Liver Diseases

Liver transplantation (LT) is the treatment of choice for end‐stage autoimmune liver diseases. However, the underlying disease may recur in the graft in some 20% of cases. The aim of this study is to determine whether LT using living donor grafts from first‐degree relatives results in higher rates of recurrence than grafts from more distant/unrelated donors. Two hundred sixty‐three patients, who underwent a first LT in the Toronto liver transplant program between January 2000 and March 2015 for autoimmune liver diseases, and had at least 6 months of post‐LT follow‐up, were included in this study. Of these, 72 (27%) received a graft from a first‐degree living‐related donor, 56 (21%) from a distant/unrelated living donor, and 135 (51%) from a deceased donor for primary sclerosing cholangitis (PSC) (n = 138, 52%), primary biliary cholangitis (PBC) (n = 69, 26%), autoimmune hepatitis (AIH) (n = 44, 17%), and overlap syndromes (n = 12, 5%). Recurrence occurred in 52 (20%) patients. Recurrence rates for each autoimmune liver disease were not significantly different after first‐degree living‐related, living‐unrelated, or deceased‐donor LT. Similarly, time to recurrence, recurrence‐related graft failure, graft survival, and patient survival were not significantly different between groups. In conclusion, first‐degree living‐related donor LT for PSC, PBC, or AIH is not associated with an increased risk of disease recurrence.