Jorge Ortiz de Urbina

Factors influencing change in health‐related quality of life after liver transplantation

Abstract:  Objective:  To assess health‐related quality of life (HRQoL) in patients following liver transplantation and the factors associated with HRQoL variation.

Encephalitis Caused by Human Herpesvirus-6 in a Liver Transplant Recipient

Encephalitis Caused by Human Herpesvirus-6 in a Liver Transplant Recipient Miguel Montejo a, Jose Ramon Fernandez b, Milagros Testillano b, Andres Valdivieso c, Koldo Aguirrebengoa a, Carmen Varasd, Alberto Olaizola e Jorge Ortiz De Urbina c Divisions of a Infectious Diseases, bHepatology, cLiver Transplantation Surgery, dDermatology Service, and eEmergency Service, Hospital de Cruces, Bilbao, Spain

A prospective randomized open study in liver transplant recipients: Daclizumab, mycophenolate mofetil, and tacrolimus versus tacrolimus and steroids

This open‐label, randomized study compared the efficacy of a regimen of corticosteroids and tacrolimus (standard therapy group, n = 79) with a regimen of daclizumab induction therapy in combination with mycophenolate mofetil and tacrolimus (modified therapy group, n = 78) in primary liver transplant recipients. The primary endpoint was biopsy‐proven acute rejection (BPAR) at 24 weeks. Secondary endpoints included time to rejection and patient and graft survival. The incidence of BPAR was significantly reduced in the modified therapy group compared to the standard therapy group (11.5% versus 26.6%, respectively, P = 0.017). The time to rejection was significantly shorter in the standard therapy group compared with the modified therapy group (P = 0.044). There was no significant difference between groups in patient or graft survival. Hepatitis C virus–positive patients exhibited no differences from hepatitis C virus–negative patients with respect to the incidence of BPAR. A steroid‐sparing regimen of daclizumab, mycophenolate mofetil, and tacrolimus was effective and well tolerated in the prevention of BPAR in adult liver transplant recipients in comparison with a standard regimen of tacrolimus and steroids. Liver Transpl 15:1542–1552, 2009.

Daclizumab induction and maintenance steroid-free immunosuppression with mycophenolate mofetil and tacrolimus to prevent acute rejection of hepatic allografts

Steroid‐free immunosuppressive regimens reduce corticosteroid‐related side effects in liver transplant recipients although their efficacy is very variable. We evaluated the efficacy and safety of a steroid‐free regimen in a 6‐month, open‐label, multicenter, pilot study, which involved 102 liver transplant patients treated with daclizumab (2 mg/kg within 6 h following transplant and 1 mg/kg on day 7), mycophenolate mofetil (MMF, 1 g b.i.d) and tacrolimus (trough levels of 5–15 ng/ml in the first month and 5–10 ng/ml thereafter). One intra‐operative dose of methylprednisolone was administered. At 6 months, the acute rejection rate was 9.8%, and patient and graft survival rates were 96% and 95%, respectively. Acute rejection rates were similar for hepatitis C‐positive patients (8.6%) and hepatitis C‐negative patients (10.4%). Infections occurred in 22% of patients; most cases were considered mild or moderate. Post‐transplantation hypertension and diabetes mellitus developed in 37% and 14% of patients, respectively, during the study period, but were markedly less frequent (8% and 6%, respectively) at 6 months. Hypercholesterolemia was observed in only 2% of patients. In conclusion, the steroid‐free immunosuppressive regimen of daclizumab, MMF, and tacrolimus effectively prevents acute rejection after liver transplantation without decreasing safety.

An open, randomized, multicenter clinical trial of oral tacrolimus in liver allograft transplantation: A comparison of dual vs. triple drug therapy

Triple therapy combining an anticalcineurin agent, corticosteroids, and azathioprine (AZA) in liver transplantation has been frequently applied, particularly in Europe. Debates have arisen concerning the use of a third drug (AZA), mainly in patients receiving tacrolimus (TAC). An open‐label, multicenter, prospective, and randomized trial was performed to assess the efficacy and safety of TAC and corticosteroids (dual therapy [D]) vs. TAC, corticosteroids, and AZA (triple therapy [T]) in liver transplantation. A total of 180 patients were randomized, 92 in D and 88 in T group. Patients were followed during 3 months for efficacy and safety and up to 24 months for patient and graft survival assessments. The rate of biopsy‐proven acute rejection was higher in D than in T group (40.7% vs. 24.4%; P = 0.021). A higher incidence of positive HCV status in D group (55.6% vs. 40.7%; P = 0.049) may explain this difference, since significantly more patients of this HCV subpopulation experienced acute rejection when treated with D therapy (48% vs. 20%; P = 0.008). No treatment differences were apparent for HCV‐negative patients. The 24‐month graft survival tended to be inferior in T group, 69.8% vs. 75.8% (P = 0.283). Similar results were observed regarding patient survival at the same time point, with values of 72.9% vs. 76.9% (P = 0.573), favoring D group. Both regimens showed comparable safety profiles with the exception of hematological abnormalities, which were more frequently observed in T group. In conclusion, both regimens were shown to be effective although increased toxicity and a trend towards a lower graft and patient survival were observed in T group. (Liver Transpl 2005;11:515–524.)

Use of artificial intelligence as an innovative donor-recipient matching model for liver transplantation: Results from a multicenter Spanish study

BACKGROUND & AIMS There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. METHODS 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. RESULTS Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and -loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN=0.80 vs. -MELD=0.50; -D-MELD=0.54; -P-SOFT=0.54; -SOFT=0.55; -BAR=0.67 and -DRI=0.42) and NN-MS (AUROC-ANN=0.82 vs. -MELD=0.41; -D-MELD=0.47; -P-SOFT=0.43; -SOFT=0.57, -BAR=0.61 and -DRI=0.48). CONCLUSIONS ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models.

Reducing the incidence of incisional hernia after liver transplantation

Two important issues must be considered when deciding the abdominal incision for a liver transplant (LT): a good access to both liver lobes and a reduced rate of woundrelated morbidity. Historically, two incisions have been recommended for a LT: the classic Mercedes incision [1] and the subcostal bilateral incision [2]. Nevertheless, in recent years, the right subcostal incision with medial extension to xyphoid process (J-shaped incision) has arisen as a good option for liver surgery [3]. The reported frequencies of incisional hernia after LT range from 4.9% to 17.2% and several factors such as older age, acute rejection with steroids treatment, ascites or wound infection seem to be associated [4–7]. In a recent article from UCLA, an incidence of 4.6% of incisional hernia was reported after LT through a Mercedes incision [4]. The authors found that reoperation, pulmonary complications and the male gender were associated risk factors for incisional hernia. Comparing the outcome using the J-shaped incision and the classic Mercedes incision for LT, Heisterkamp et al. [8] found a significantly lower incidence of incisional hernia after the J-shaped incision (7% vs. 24% P = 0.002) with a relaparotomy rate that was not significantly different between the two groups (31% and 45% respectively P = 0.487). From January 1998 to December 2007, we performed 626 consecutive orthotopic liver transplantations. All patients were transplanted using a bilateral subcostal incision that was closed with two layers of running sutures of absorbable monofilament (Maxon 1; Synature, Covidien, Mansfield, USA). Child-Pugh score was A in 141 patients (22.5%), B in 242 (38.7%), and C in 243 (38.8%). Immunosuppression was based on tacrolimus, and steroids from the first post-transplant day (20 mg/day of prednisone). A 3-day course of methylprednisolone was used in 83 patients (13.2%) to treat a moderate or severe acute cellular rejection. Post-transplant relaparotomy was needed in 29 patients (4.6%). No patient was lost to follow-up. An incisional hernia was diagnosed, and subsequently treated in 11 patients, which means an incidence of 1.7%. The Chi-squared test was used to compare our results with the two reports already mentioned [4,8]. Our incidence of incisional hernia was significantly lower with a P value ranging from 0.03 to 0.003 depending on the type of incision, J-shaped or Mercedes. In our opinion, this significantly low incidence of incisional hernia may be explained by several circumstances: (i) the avoidance of Mercedes incision and its relative ischemic area at the trifurcation point, (ii) the low accumulated steroid dose in our patients because of our immunosuppressive protocol and the low rate of steroids-treated acute cellular rejection, and (iii) the significant low incidence of posttransplant relaparotomy (P < 0.001 when compared with the reports previously mentioned [4,8]). According to our results, subcostal bilateral incision may be considered for liver transplantation provided other risk factors for incisional hernia are prevented. Incisions with upward midline extension may be reserved for liver transplants with difficult suprahepatic vein reconstruction, as they allow a vertical access to the suprahepatic vena cava rather than from a caudal view [9].

Cardiovascular morbidity and mortality after liver transplantation: The protective role of Mycophenolate Mofetil

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow‐up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre‐LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate‐free immunosuppressive therapy, increased post‐LT CV morbidity and mortality. The development of new‐onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post‐LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498–509 2017 AASLD.

Análisis farmacoeconómico del tratamiento hemostático en cirugía con una esponja medicamentosa de fibrinógeno y trombina

ResumenObjetivo: Comparar la eficiencia de una esponja medicamentosa con fibrinógeno y trombina (EFT, TachoSil®) para mejorar la hemostasia en cirugía hepática y pulmonar, cuando las técnicas estándares son insuficientes. Métodos: Diseño: análisis de costes y efectos. Efectividad y utilización de recursos: se estimó a partir de ensayos clínicos aleatorizados en cirugía pulmonar y hepática en comparación con una solución de fibrinógeno y trombina humana (SFT, Tissucol Duo®) y con el coagulador de argón. Perspectiva: Sistema Nacional de Salud (costes directos sanitarios). Costes: se estimaron los costes diferenciales: costes de adquisición, tiempo de preparación y aplicación de los fármacos y, en cirugía pulmonar, coste de los días adicionales de hospitalización por pérdidas de aire postquirúrgicas. Caso básico: valores medios de los costes. Análisis de sensibilidad: análisis simple unifactorial, con los valores extremos de los costes. Resultados: Efectividad en cirugía pulmonar: pérdidas secundarias de aire después de la resección pulmonar: EFT: 25% y 36,4%; SFT/coagulador de argón: 33% y 37%, respectivamente. El número de pacientes que era necesario tratar con la EFT fue de 9 y 46 pacientes, respectivamente. Efectividad en cirugía hepática: tiempo de hemostasia intraoperatoria: EFT 3,9 y 3,6 minutos; coagulador de argón 6,3 y 5,0 minutos. Costes incrementales por intervención (coste con SFT-coste con EFT). Cirugía pulmonar: 133,34 €. Cirugía hepática: 187,66 €. Análisis de sensibilidad: en todos los casos la utilización de EFT redujo los costes por intervención. Conclusiones: La utilización de la EFT es un procedimiento más eficiente que la utilización de una SFT o el coagulador de argón en cirugía hepática o pulmonar.

Favorable longterm outcomes of liver transplant recipients treated de novo with once-daily tacrolimus: Results of a single-center cohort.

The once‐daily prolonged‐release formulation of tacrolimus has been recently related with significant graft and patient mid‐term survival advantages; however, practical information on the de novo administration after liver transplantation and longterm outcomes is currently lacking. This study is a 5‐year retrospective analysis of a single‐center cohort of liver transplant recipients treated de novo with once‐daily tacrolimus (April 2008/August 2011). The study cohort consisted of 160 patients, including 23 with pretransplant renal dysfunction, with a median follow‐up of 57.6 months (interquartile range, 46.6‐69.0). Tacrolimus target trough levels were 5‐10 ng/mL during the first 3 months after transplant, reducing progressively to <7 ng/mL after the first posttransplant year. Once‐daily tacrolimus was withdrawn in 35 (21.8%) patients during follow‐up, mostly due to renal dysfunction and/or metabolic syndrome. The biopsy‐proven acute rejection rate was 12.5% with no cases of steroid‐resistant rejection. The cumulative incidence of de novo diabetes, hypertension, and dyslipidemia were 16.9%, 31.2%, and 6.5%, respectively. Hepatocellular carcinoma recurrence rate was 2.8%. Renal function remained stable after the sixth month after transplant with a mean estimated glomerular filtration rate of 77.7 ± 19.6 mL/minute/1.73 m2 at 5 years. None of our patients developed chronic kidney disease stage 4 or 5. Patient survival at 1, 3, and 5 years was 96.3%, 91.9%, and 88.3%, respectively. Overall survival of patients with Model for End‐Stage Liver Disease (MELD) score > 25 points was not significantly different. In conclusion, our study suggests that immunosuppression based on de novo once‐daily tacrolimus is feasible in routine clinical practice, showing favorable outcomes and outstanding longterm survival even in patients with high MELD scores. Liver Transplantation 22 1391–1400 2016 AASLD.