S. Olivares Pizarro

Hospital Universitario Rey Juan Carlos

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Manuel Abradelo de Usera

Research Institute Hospital 12 de Octubre

Rebeca Sanabria Mateos

King's College Hospital

Carlos Jiménez Romero

Universidad Complutense de Madrid

C. Alegre

Hospital Universitario 12 De Octubre

ÁG

Álvaro García‐Sesma

Hospital Universitario 12 De Octubre

Alejandro Manrique Municio

Hospital Universitario 12 De Octubre

Iago Justo

Universidad Complutense de Madrid

Jorge Calvo

Universidad Complutense de Madrid

Félix Cambra Molero

Research Institute Hospital 12 de Octubre

Elfrid Cifuentes

Research Institute Hospital 12 de Octubre

Cooperative Institutions

University of Birmingham

University of Cagliari

Collaborative Group (United States)

Vall d'Hebron Hospital Universitari

University of Campania "Luigi Vanvitelli"

Sapienza University of Rome

NIHR Birmingham Biomedical Research Centre

Istituti di Ricovero e Cura a Carattere Scientifico

Yorkshire Cancer Research

Urology Foundation

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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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Immunosuppressive Monotherapy with Everolimus in Liver Transplantation

Transplantation (2012)

C. Alegre Carlos Jiménez Romero Manuel Abradelo de Usera Jorge Calvo Félix Cambra Molero

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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MP721A DECREASE IN INTACT PARATHYROID HORMONE (iPTH) LEVELS IS ASSOCIATED WITH HIGHER MORTALITY

Nephrology Dialysis Transplantation (2017)

Esmeralda Castillo-Rodríguez Laura Rodríguez-Osorio S. Olivares Pizarro Raquel Esteras Raúl Fernández

ENG and REC patients using Student's t test or chi squared test as appropriate.Seroconversion rates were compared between the two vaccines using chi squared test.RESULTS: ENG patients (N = 24,677) were older (63. 9 vs. 63.1 years), had a higher eKt/V (1.6 vs. 1.5), a higher proportion of diabetics (61.5% vs. 54.9%),fewer patients with congestion heart failure (12.3% vs. 16.1%),lower dialysis vintage (0.8 vs. 1.1 years) and lower hemoglobin (11.2 vs. 11.5 g/dL) compared to REC patients (N = 1,320) (Table 1).Seroconversion rates were significantly higher with ENG compared to REC (1st series: 73.7% vs. 64.3%,D=9.4% 95% CI: 6.7 % to 12.1%); 1st and 2nd series combined: 78.5% vs. 64.6%,D=13.9%, 95% CI: 11.2% to 16.5%) (Figure 1).CONCLUSIONS: When administering full vaccination courses as outlined above, Engerix-B yields substantially higher primary seroconversion rates than Recombivax-HB.The same is true when looking at cumulative response rates for the 1 st and 2 nd series combined.These results hold true even after adjusting for differences in population characteristics.Reference 1)Rustgi VK., Comparative study of the immunogenicity and safety of Engerix-B administered at 0, 1, 2 and 12 months and Recombivax HB administered at 0, 1, and 6 months in healthy adults.Vaccine.

10.1093/ndt/gfx180.mp721

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Sirolimus Monotherapy in Liver Transplant Recipients with De Novo Tumors

Transplantation (2012)

C. Alegre Carlos Jiménez Romero Alejandro Manrique Municio Elfrid Cifuentes Félix Cambra Molero

Background: Sirolimus is a macrocyclic antibiotic with antifungal, antifibrotic and immunosuppressive properties that can inhibit metastatic tumor growth and angiogenesis in vivo mouse models. It can be used as a substitute for calcineurin inhibitors (CNI) because it may reduces the likelihood of recurrent hepatocellular carcinoma (HCC) or the rate of de novo tumors in high risk transplant patients. Sirolimus protects allografts from rejection while simultaneously inhibits tumor growth. Patients and methods: Between April 1986 and December 2010 we performed 1500 orthotopic liver transplants (OLT). Fifty-seven patients received immunosuppressive treatment with sirolimus, and 26 patients of them due to de novo tumors. Currently, 20 of these patients are with sirolimus monotherapy. We analyze the outcome of liver transplant recipients who developed de novo tumors and were treated with sirolimus monotherapy. Results: There were 20 patients (18 males and 2 females), with a mean age at OLT of 50.3±12.1 years, and mean follow-up of 111.5 months. The main indications for OLT were alcoholic cirrhosis (40%), and HCV cirrhosis (15%). The most frequently immunosuppressive therapy used at discharge was tacrolimus+prednisone (55%). Premonoterapy immunosuppression most frequently used was tacrolimus+sirolimus (50%), and mycophenolate+sirolimus (40%). The mean time from OLT to sirolimus treatment was 74.6 months, and from then until the beginning of monotherapy was 9.5 months with a mean time of 24.7 months in monotherapy. The location of de novo tumors was: aerodigestive tract (45%), skin (20%), lymphoproliferative disorders (15%), urologic tract (10%), gynecological (5%), and central nervous system (5%). There was only one case of rejection (5%) in the presence of adequate drug levels, successfully treated with reintroduction of tacrolimus. Adverse effects were seen in 80% of patients, and the most frequent were: dyslipidemia (11 patients), edema (5 patients), and oral thrush (4 patients). Regarding lipid profile, mean cholesterol value before sirolimus was 168 mg/dl, and postmonotherapy was 211 mg/dl (p =0.0001). Seven patients are treated with hypolipemiant. Mean value of pre-sirolimus triglycerides was 104 mg/dl and post-monotherapy was 130 mg/dl (p=0.071). Regarding renal function, mean creatinine clearance pre-sirolimus was 70.6 ml/min and post-monotherapy was 75.6 ml/min (p>0.05). Conclusions: Sirolimus is a potent immunosuppressant with antitumoral properties, with low rate of rejection, which represents a good option OLT with de novo malignancies. More than half of the patients presented side effects, but they were well tolerated or controlled with medical treatment (dyslipidemia as the most frequent). There was an improvement of renal function showing an increase in creatinine clearance.

Sirolimus

Immunosuppression

10.1097/00007890-201211271-00083

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Rapid decline of anti-SARS-CoV-2 antibodies in patients on haemodialysis: the COVID-FRIAT study

Clinical Kidney Journal (2021)

Roberto Alcázar Arroyo José Pórtoles Paula López–Sánchez Felipe Zalamea Karina Furaz

Coronavirus disease 2019 (COVID-19) patients on haemodialysis (HD) have high mortality. We investigated the value of reverse transcription polymerase chain reaction (RT-PCR) and the dynamic changes of antibodies (enzyme-linked immunosorbent assay immunoglobulin M (IgM) + IgA and/or IgG) in a large HD cohort.We conducted a prospective observational study in 10 Madrid HD centres. Infection rate, anti-SARS-CoV-2 antibody dynamics and the incidence of asymptomatic SARS-CoV-2 infection (defined by positive RT-PCR, IgM + IgA and/or IgG) were assessed.From 1 March to 15 April 2020, 136 of 808 (16.8%) HD patients were diagnosed with symptomatic COVID-19 by RT-PCR of nasopharyngeal swabs and 42/136 (31%) died. In the second fortnight of April, RT-PCR and anti-SARS-CoV-2 antibodies were assessed in 763 of the surviving patients. At this point, 69/91 (75.8%) symptomatic COVID-19 patients had anti-SARS-CoV-2 antibodies. Four weeks later, 15.4% (10/65) of initially antibody-positive patients had become negative. Among patients without prior symptomatic COVID-19, 9/672 (1.3%) were RT-PCR positive and 101/672 patients (15.0%) were antibody positive. Four weeks later, 62/86 (72.1%) of initially antibody-positive patients had become negative. Considering only IgG titres, serology remained positive after 4 weeks in 90% (54/60) of patients with symptomatic COVID-19 and in 52.5% (21/40) of asymptomatic patients. The probability of an adequate serologic response (defined as the development of anti-SARS-CoV-2 antibodies that persisted at 4 weeks) was higher in patients who had symptomatic COVID-19 than in asymptomatic SARS-CoV-2 infection {odds ratio [OR) 4.04 [95% confidence interval (CI) 2.04-7.99]} corrected for age, Charlson comorbidity index score and time on HD. Living in a nursing home [OR 5.9 (95% CI 2.3-15.1)] was the main risk factor for SARS-CoV-2 infection.The anti-SARS-CoV-2 antibody immune response in HD patients depends on clinical presentation. The antibody titres decay earlier than previously reported for the general population. This inadequate immune response raises questions about the efficacy of future vaccines.

2019-20 coronavirus outbreak

Betacoronavirus

10.1093/ckj/sfab048

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Citations (32)

Favorable outcome with ketoconazole in Candida septic arthritis.

PubMed (1992)

S. Olivares Pizarro Leonor Barile A Fraga Frédéric Medina

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Citations (6)

Inequalities in screening policies and perioperative protection for patients with acute appendicitis during the pandemic: Subanalysis of the ACIE Appy study