Background: Everolimus is a potent immunosuppressant which have several advantages over calcineurin inhibitors (CNI): good tolerance, preventive effects on cardiovascular morbidity and mortality, as well as cancer prevention due to cell proliferation inhibition. It is particularly suitable for patients with liver transplant due to hepatocellular carcinoma (HCC), de novo malignancies or renal insufficiency. We analyze our experience with the use and management of everolimus monotherapy in orthotopic liver transplantation (OLT). Patients and methods: Between April 1986 and December 2010 we performed 1500 OLT in our institution. Everolimus was introduced into clinical use at the end of 2005. Fifty-seven patients received immunosuppression with everolimus, and 24 of these are currently in monotherapy. We analyze side effects, acute rejection, renal insufficiency, lipid profile as well as tolerance and indication for use. Results: There were 19 males (79.2%) and 5 females (20.8%). The main indication for OLT was alcoholic cirrhosis in 6 patients (25%), and other indications were HCV, HBV and HCC. Hepatocellular carcinoma (37.5%), lymphoproliferative diseases (21%), and de novo digestive and respiratory tract tumors (21%) were the main causes of switching to everolimus. The majority of our patients (54.2%) received tacrolimus+prednisone as initial immunosuppressive therapy, initiating monotherapy with everolimus at a mean time of 71.8 months after OLT. The mean follow-up after switching to everolimus monotherapy was 10.3 months. There were no differences in terms of renal or hepatic functions after everolimus monotherapy. We found lipid profile higher in comparison with it before everolimus: mean cholesterol level before everolimus was 170 mg/dl and 175 mg/dl after; mean triglycerides before monotherapy was 103 mg/dl and 135 mg/dl after. Eight patients are treated with hypolipemiants. Mean creatinine clearance rate (CCL) premonotherapy was 70.42 ml/min, and postmonotherapy was 76.24 ml/min (p=0.091). There was only one patient who showed acute rejection in the presence of adequate drug levels, successfully treated with tacrolimus reintroduction. Adverse effects were observed in 15 patients (62.5%), and the most frequent were dyslipidemia (8 patients) and edemas (5 patients). Conclusions: Everolimus monotherapy is a good immunosuppressive option in OLT patients with recurrent or de novo malignancies, or with renal dysfunction. Everolimus monotherapy is associated with low rejection rate and improvement of renal function. The most frequent side effects are hyperlipidemia and edemas, but usually well tolerated by the patients or controlled with pharmacological treatment.

Everolimus

10.1097/00007890-201211271-00084

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Sirolimus Monotherapy in Liver Transplantation

Transplantation (2012)

C. Alegre Carlos Jiménez Romero Manuel Abradelo de Usera Alejandro Manrique Municio Elfrid Cifuentes

Background: Sirolimus is an antibiotic with antifungal, antifibrotic and immunosuppressant properties that has been used in orthotopic liver transplantation (OLT) as substitute of calcineurin inhibitors (CNI) in cases of de novo tumors, patients subjected to OLT for hepatocellular carcinoma (HCC) and nephrotoxicity due to CNI. We present our experience with sirolimus monotherapy in OLT Patients and methods: Between April 1986 and December 2010 we performed 1500 OLT, of whom 57 patients are receiving immunosuppressive treatment with sirolimus, and 39 of them are currently in monotherapy. We analized the clinical characteristics of patients, associated side effects, rejection rate, renal function and lipid profile, in patients treated with sirolimus monotherapy. Results: There were 31 males (79.5%), and 8 females (20.5%) with a mean age at OLT of 50.5 ±10.5 years. The mean follow-up period was 89.8 months. The main indications for OLT was alcoholic cirrhosis in 10 patients (25.6%), HCV cirrhosis in 5 (12.8%), and HCV cirrhosis+HCC in 5 (12.8%). Other causes were HBV cirrhosis, acute liver failure, autoimmune hepatitis. The most frequently immusosuppressive therapy used at discharge was tacrolimus+prednisone in 25 patients (64.1%). Premonotherapy immunosuppression most frequently used was tacrolimus+sirolimus in 21 patients (53.9%), and mycophenolate+sirolimus in 15 (38.5%). The mean time from OLT to sirolimus monotherapy treatment initiation was 65.3 months, and the mean follow-up after switching to sirolimus monotherapy was 22.8 months. Only 1 patient (2.6%) presented acute rejection, being with adequate drug levels, and treated with reintroduction of tacrolimus. The indications for conversion to sirolimus monotherapy were: de novo aerodigestive tract tumors in 11 patients (28.3%), HCC in 10 (25.6%), nephrotoxicity due to CNI in 5 (12.8%), skin malignacies in 4 (10.3%), lymphoproliferative disorders in 3 (7.7%), urologic tract tumors in 3 (7.7%), central nervous system tumors in 2 (5%) and gynecological in 1 patient (2.6%). Adverse effects developed in 35 patients (89.7%) and the most frequent were: dyslipidemia in 24 patients (61.5%), edemas in 8 (20.5%), and cytopenias in 8 (20.5%). The mean creatinine clearance rate (CCL) before sirolimus therapy was 69.9 ml/min (normal kidney function in 30.8% of patients, mild renal insufficiency in 48.7%, and moderate in 20.5%); and after monotherapy was 75.3 ml/min (normal kidney function in 38.5% of patients, mild renal insufficiency in 41%, moderate in 18%, and severe in 2.6%) (p=0.0001). Total cholesterol and trigliceride values increased significantly after switching: cholesterol 171 mg/dl vs 208 mg/dl (p=0.002); and trigliceride 108 mg/dl vs 158 mg/dl (p=0.015). Seventeen patients were treated with hypolipemiant drugs. Conclusions: Sirolimus monotherapy is a good immunosuppressive option in patients who underwent OLT for HCC or those who develop de novo tumors or nephrotoxicity due to CNI. Monotherapy is well tolerated and is associated with low rejection rate. Renal function improves after conversion to sirolimus monotherapy and dyslipidemia is pharmacologically well controlled.

Sirolimus

Immunosuppression

10.1097/00007890-201211271-00081

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Use of Norepinephrine in Pancreas Donors and its Influence on Patient and Graft Survival

Transplantation (2018)

Alberto Marcacuzco Alejandro Manrique Municio Iago Justo Oana Anisa Nutu Félix Cambra Molero

Introduction Brain death originates a vasomotor center dysfunction, a decrease in catecholamine release and finally vasodilatation secondary to the decrease of the peripheral vascular resistence. To this we should add the relative dehydration resulting from a mixture of previous water restriction and polyuria secondary to vasopresin deficiency that will originate hypovolemia and hypotension in a potential donor. Because the most important factor in the viability and graft function is adequate donor perfusion, it has been postulated that donor catecholamines administration might have a beneficial effect on kidney function, while its effect on other organs is unknown. The aim of this study was to determine if norepinephrine in the donor is associated with recipient and pancreatic graft survival. Methods We performed a retrospective and comparative study, between the patients transplantated with a pancreatic graft proceeding from a donor where norepinephrine was used (Group A) and patients transplantated with a graft where norepinephrine was not used (Group B). Results 165 patients that underwent simultaneous pancreatic-kidney transplantation were included. The mean recipient age was 38.9 years, while the donor age was 28.6 years. 58.4% of the donors and 66.5% of the recipients were men. Grafts from group A presented an adequate function in 69% of the cases (p=0.03). The patient actuarial survival at 1.3 and 5 years in group A was: 94.9%, 93.3% and 92.5% respectively and in group B: 96.6%, 89.5% and 89.5% (p=0.6). The graft actuarial survival in group A was 82.8%, 78.9%, 72.9%, as compared to 75,9%, 68,4% and 63,8% respectively in group B (p=0.05). Conclusion Pancreatic grafts proceeding from donors who received norepinephrine present a significantly increased graft survival compared to grafts proceeding from donors without norepinephrine. No differences were seen in the patient survival between both groups.

10.1097/01.tp.0000543747.25842.b3

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Histologic Evaluation of Post-implantation Immediate C4d Deposition in 13 Intestinal Grafts: Correlation With Cell-based Crossmatching, Cold Ischemia Time, and Preservation Injury

Transplantation Proceedings (2014)

Patricia Lucía López-García Jorge Calvo Francisco Colina Claudio Ballestín Carcavilla Carlos Jiménez‐Romero

10.1016/j.transproceed.2014.06.028

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Octogenarian Liver Grafts Reaching Centennial Age After Transplantation

Transplantation (2017)

Luis Carlos Jiménez-Romero Óscar Caso Maestro Félix Cambra Molero Alejandro Manrique Municio Jorge Calvo

Several octogenarian liver graft series and even isolated cases of nonagenarian liver grafts have been reported.1,2 To our knowledge, there is no reported information about octogenarian grafts reaching centennial age after LT while maintaining a normal liver function. From April 1986 to October 2016, we performed 1870 LT at our institution. In 58 recipients, we used octogenarian liver grafts, and at present, 4 of these livers have reached or surpassed a total lifespan of 100 years. Three recipients are currently alive and well with normal liver function, and the fourth recipient died 11 years after LT because of renal failure and coronary disease, but with normal liver function and histology (Table 1).TABLE 1: Characteristics of octogenarian liver grafts reaching centennial age after LTThe blood flow, synthetic, excretory, and metabolic changes of liver function are affected by aging, and these consequences may have clinical relevance.3 After the age of 50 years, the liver becomes progressively smaller, so that it decreases from 2.5% of total body weight in young people to about 1.6% in the nonagenarian population, and several morphological changes with aging indicate that the liver cells in advanced old age are in a hyperfunctioning state, possibly trying to compensate for the decline in total cell number.4 However, it has been suggested that aging has a limited effect on liver functions but more on its response to extrahepatic factors,5 disease states or increased metabolic demands to which elderly people may have an impaired ability to respond.4 Atheromatosis usually affects the celiac trunk in old donors but, although this happens rarely, when atheroma occurs distally at the level of the right hepatic artery or at the bifurcation of the gastroduodenal and the common hepatic artery, the liver graft must be discarded for LT.2 The LT procedure is a scenario in which many donor risk factors may be involved. Thus, in our previous brief communication on octogenarian liver donors, we recommended the use of liver grafts with no age limit but in good preprocurement condition (hemodynamic stability, low doses of vasopressor drugs), short intensive care unit stay, good liver function tests, soft liver consistency, absence of hepatic artery atheromatosis, cold ischemia time less than 9 hours, and macrosteatosis less than 30%.1 From that time, we have continued applying the same criteria, but in recent years we have added other conditions such as implanting the octogenarian livers into recipients without Hepatitis C virus (HCV) cirrhosis and model for end-stage liver disease scores lower than 20 who could tolerate well a probable transient graft dysfunction.2 As we have seen in this short experience, it is possible that an octogenarian liver graft can reach the centennial age after transplant while the recipient maintains a normal liver function and a good quality of life if a good donor selection is done, and recipients with HCV cirrhosis or advanced liver disease are excluded, but at present, with the current introduction of new anti-HCV drugs, we are also using these older donors in HCV recipients to decrease the waiting list mortality. However, further investigations are needed to demonstrate good results using octogenarian liver donors in HCV recipients.

Centennial

Liver disease

Liver function

10.1097/tp.0000000000001772

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Citations (9)