Immunosuppression and Tolerance in Adult Liver Transplantation. A literature review on the immunosuppression-drugs after a liver transplantation; how to best provide safe treatment and good quality of life.

Background: There is increasing interest in long-term management issues in liver transplantation recipients; quality of life, complications related to extended immunosuppressants, natural development of co-morbidities and recurrent disease. IS agents are used in induction of the liver transplantation, maintenance of the organ, and reversal of organ rejection. Aim: A systematic literature search with the purpose of summaries the existing clinical research on this specific topic; immunosuppressive medications post-liver transplantation. Material and methods: Search method in PubMed; Medical Subject Headings, with the terms: ("Liver Transplantation"[Mesh]) AND "Immunosuppression" [Mesh]. The selected studies were assessed for scientific quality and relevance for the thesis. Results: Steroid-based IS are responsible for a substantial post-LTx morbidity and mortality, hence, minimization of its use is of utmost importance to improve patient’s quality of life. Because of systemic steroids impact on all organs in the human body and all its side effects that increases risk factors of morbidity. It is important to comprehend the hepatic disease and the patient, as well as understanding the efficacies and side effects/interactions of IS medication. This way the doctor and the patient can strike a balance between suppression of rejection and minimization of side effects. The patient group are very complex, and this have been shown to be a challenge when it comes to comparing the result on the effect of different studies with different immunosuppression’s as the reason for liver failure have a lot to say for graft rejection and patient survival, especially for complication accruing with lifelong IS. Conclusion: LTx recipients are an inherently complex population, with diverse and serious underlying medical concerns that have the potential to adversely affect posttransplant outcomes, thus would a general IS therapy lead to a greater rejection rate. There is a need for more clinical studies, random control trails, that can help us finding the best immunosuppressive treatment for liver transplanted patients

Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES: To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES: Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS: Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS: Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. LIMITATIONS: The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. CONCLUSIONS: TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013544. FUNDING: The National Institute for Health Research HTA programme.The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 09/119/01. The protocol was agreed in July 2014. The assessment report began editorial review in May 2015 and was accepted for publication in October 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health

Prevention, Diagnosis and Treatment of Acute Kidney Transplant Rejection

Kidney transplant rejection is complex clinical problem with long-lasting consequences for the patient. The focus of this thesis is optimization of the maintenance immunosuppressive therapy, diagnosis and treatment of kidney transplant rejection. The conclusions of this thesis are: __i)__ belatacept remains a promising immunosuppressive drug for subgroups of kidney transplant recipients, for instance in patients with post-transplantation diabetes mellitus, but a more tailored st

Optimizing immunosuppression with mTOR inhibitors in renal transplant recipients

The aim of this thesis was to optimize immunosuppressive therapy, especially everolimus therapy in renal transplantation recipients by identifying pharmacological and pharmacogenetic risk factors influencing pharmacokinetics, and dynamics such as side effects and patient outcome. Therapeutic Drug Monitoring (TDM) of oral immunosuppressive agents is essential to prevent toxicity and or rejection; therefore it is very important to use a reliable and accurate bioanalytical assay. Differences between the most used analytical assays of measuring everolimus in whole blood and its effect on dosing advice were investigated. TDM is performed based on either trough or AUC monitoring and pharmacogenetics might be a valuable addition to TDM. Therefore the population pharmacokinetics of everolimus in a calcineurin free regimen was investigated and predictive factors such as pharmacogenetics were evaluated. In addition a limited sampling model was developed. MTOR inhibitors are known for a variety of side effects and high dropout rates. In this thesis a comprehensive analysis was performed aimed at identifying risk factors for discontinuation and a number of serious side effects. This thesis also describes an analysis aimed at identifying risk factor associated with delayed graft function, acute rejection and subclinical rejection in patients on a cyclosporine based immunosuppressive regimen.Nederlandse Transplantatie Vereniging de Nierstichting AZL ontwikkelingskrediet (OOK) Apotheek Afdeling Nierziekten LUMCUBL - phd migration 201

Replikation von Epstein-Barr-Virus, Cytomegalievirus und Humanem Polyomavirus bei Patienten nach Nierentransplantation unter Immunsuppression mit Belatacept

Infektionen nach Organtransplantation unter Immunsupression stellen eine der größten Herausforderungen der Transplantationsmedizin dar. Besonders virale Infekte sind durch eingeschränkte Therapieoptionen schwer behandelbar und haben einen Einfluss auf Transplantat- und Patientenüberleben. In der Nachsorge der Nierentransplantation sind besonders EBV, CMV und BKV von Bedeutung. Belatacept ist ein neues Immunsuppressivum, das eine Alternative zu der Immunsuppression durch Calcineurininhibitoren darstellt. Die vorliegende Arbeit vergleicht ein Belatacept-basiertes immunsuppressives Regime mit der Standardimmunsuppression, hinsichtlich der Replikation von EBV, CMV und BKV. Bei der zugrunde liegenden Studie handelt es sich um eine retrospektive Datenanalyse von 91 Patienten, die Belatacept erhielten und 91 Kontrollpatienten, die ein anderes immunsuppressives Regime erhielten. Virologische Daten wurden im Zeitraum von 24 Monate vor, bis 68 Monate nach Beginn der Belataceptgabe analysiert und deskriptiv ausgewertet. Außerdem wurde die Überlebenszeitanalyse für die erste Virusreplikation nach Umstellung auf Belatacept, sowie die Ereignisse Transplantatverlust und Tod ermittelt. Die Gesamtcopyzahl betrachtend, replizierten EBV und CMV höher unter Belatacept, BKV replizierte niedriger unter Belatacept. Die Gesamtcopyzahl von EBV unter Belatacept war höher mit 277.671 cop/mL im Vergleich zur Kontrollgruppe mit 46.770 cop/mL. In der Belataceptgruppe replizierten 29/91 Patienten (31%). In der Kontrollgruppe replizierten 5/91 Patienten (5,5%) (p<0.05). Die Gesamtcopyzahl von CMV unter Belatacept war mit 6.206.010 cop/mL bei 9/91 Patienten (9,9%) deutlich höher als in der Kontrollgruppe mit 713.120 cop/mL bei 7/91 Patienten (7,7%), wobei sich die Anzahl der Patienten, die replizierten, statistisch nicht unterschied (p=0,601). Im Gegensatz dazu fiel in der BKV-Auswertung auf, dass unter Belatacept eine deutlich niedrigere Gesamtcopyzahl von BKV im Urin von 583 x 106 cop/mL zu beobachten war im Vergleich zur Kontrollgruppe mit 42.212 x 106 cop/mL. In beiden Gruppen replizierten 14/91 (15,4%) Patienten im Urin. Im Plasma fiel ein noch deutlicherer Unterschied der Replikation mit 86.660 cop/mL unter Belatacept, zu 50.025 x 106 cop/mL in der Kontrollgruppe auf. In der Belataceptgruppe hatte nur 1/91 (1,2%) Patienten eine Zusammenfassung 10 nachweisbare Plasmareplikation verglichen mit 8/91 (8,8%) Patienten in der Kontrollgruppe (p<0.05). Das Patientenüberleben war in der Belataceptgruppe signifikant schlechter mit 13 Todesfällen während des Beobachtungszeitraumes, gegenüber vier Todesfällen in der Kontrollgruppe (p<0,05). Das Ereignis Transplantatverlust trat in der Belataceptgruppe bei 18 Patienten auf, in der Kontrollgruppe bei 11 Patienten (p=0,156). Zusammenfassend zeigte die vorliegende Studie eine erhöhte Gesamtreplikationsrate für EBV und CMV unter Belatacept, sowie eine niedrigere Gesamtreplikationsrate für BKV im Vergleich zur Standardimmunsuppression. Aufgrund von niedrigerer BKV-Replikation stellt Belatacept möglicherweise damit eine Therapieoption bei BK-Nephropathie dar.Infections after transplantation under immunosuppressant therapy are one of the biggest challenges in today’s transplant medicine. During the follow-up after transplantation particularly Epstein-Barr-Virus, Cytomegalovirus and BK Virus matter. Belatacept is a new immunosuppressive drug which is an alternative to immunosuppression with Calcineurin-Inhibitors. This work compares a Belatacept-based immunosuppressive regimen with standard immunosuppression, regarding the replication of the Epstein-Barr-Virus, Cytomegalovirus and BK Virus. The underlying research is a retrospective data analysis of 91 patients with a Belatacept-based immunosuppressive regimen and 91 patients under standard immunosuppression. The virological data was descriptively analysed during the period of 24 month before, until 68 month after conversion to Belatacept. Furthermore a survival analysis was calculated of the events first virus replication after conversion to Belatacept, death and graft loss. Regarding the overall replication, Epstein-Barr-Virus und Cytomegalovirus replicated higher under Belatacept. BK Virus replicated less under Belatacept. The overall replication of Epstein-Barr-Virus in the BG was clearly higher with 277,671 cop/mL in comparison to 46,770 cop/mL in the CG. In the BG 29/91 patients (31%) replicated, in the CG 5/91 patients (5.5%) replicated (p<0.05). The overall replication of Cytomegalovirus under Belatacept was 6,206,010 cop/mL of 9/91 patients (9.9%) as opposed to 713,120 cop/mL of 7/91 patients (7.7%) in the CG, whereas the number of patients that replicated did not differ significantly (p=0.601). On the contrary, after analysis we could state that the overall replication of BK Virus in urine was considerably lower with 583 x 106 cop/mL in the BG related to the CG with 42,212 x 106 cop/mL. In both groups 14/91 (15.4%) patients replicated in urine. In plasma the difference between the two groups was even higher with 86,660 cop/mL in the BG and 50,035 x 106 cop/mL in the CG. In the BG just 1/91 patient (1.2%) had a plasma replication compared to 8/91 patients (8.8%) in the CG (p<0.05). The patient survival was significantly worse in the BG with 13 cases of death during follow up against 4 cases of death in the CG (p<0.05). 18 patients suffered from graft loss in the BG in contrast to 11 patients in the CG (p=0.156). Summarizing, our research showed a higher overall replication for Epstein-Barr-Virus, Cytomegalovirus under Belatacept, as well as a lower overall replication for BK Virus compared to the standard immunosuppression. Due to a lower replication of BK Virus Belatacept is potentially a therapy option for BK-Nephropathy

Therapeutic drug monitoring of novel immunosuppressants

Therapeutic drug monitoring is primarily undertaken for narrow therapeutic index drugs, such as immunosuppressants. These drugs have reduced the incidence of acute rejection and improved allograft survival. However, due to their narrow therapeutic index, small variations in blood levels may result in inadequate levels of immunosuppression or toxic drug concentrations. To overcome these problems individual dose regimen based-on pharmacokinetic monitoring has been proposed in the past years. Indeed, several studies have previously documented a significant association between cyclosporine whole blood levels and patient's clinical outcome, expressed as rejection episodes as well as drug-related adverse events. Novel immunosuppressive agents have been recently introduced on the market (such as rapamycins and mycophenolic acid-releasing formulations). However, data on their pharmacokinetics, which in turn could be useful for the definition of therapeutic ranges, are scanty. To address this issue we have used a chromatographic method for the measurement of mycophenolic acid levels in kidney transplant recipients. Although this immunosuppressant is usually given in a fixed daily dose regimen, we found a positive correlation between drug levels, but not dose, and renal function. As additional analysis, significant pharmacokinetic interactions between mycophenolic acid and concomitant immunosuppressive regimens have been identified. Similarly, novel chromatographic methods for the analysis of rapamycins in the whole blood have been developed in our laboratory, and applied to identify pharmacokinetic interactions between these and other immunosuppressive agents. In the last part of my research project, I have also presented preliminary data on the application of pharmacogenetics analysis in patients given cyclosporine as part of their immunosuppressive regimen. In conclusion, it can be reasonably speculated that TDM based on pharmacokinetic, as well as novel pharmacogenetic approaches, can be considered as reliable tools to guide drug dosing in organ transplantation setting, ultimately resulting in a significant improvement of long term graft and patient survival

Target of rapamycin inhibitors (TOR‐I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

Background Kidney transplantation is the therapy of choice for many patients with end‐stage kidney disease (ESKD) with an improvement in survival rates and satisfactory short term graft survival. However, there has been little improvement in long‐term survival. The place of target of rapamycin inhibitors (TOR‐I) (sirolimus, everolimus), which have different modes of action from other commonly used immunosuppressive agents, in kidney transplantation remains uncertain. This is an update of a review first published in 2006. Objectives To evaluate the short and long‐term benefits and harms of TOR‐I (sirolimus and everolimus) when used in primary immunosuppressive regimens for kidney transplant recipients. Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 20 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria All randomised controlled trials (RCTs) and quasi‐RCTs in which drug regimens, containing TOR‐I commenced within seven days of transplant, were compared to alternative drug regimens, were included without age restriction, dosage or language of report. Data collection and analysis Three authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random‐effects model. The certainty of the evidence was assessed using GRADE Main results Seventy studies (17,462 randomised participants) were included; eight studies included two comparisons to provide 78 comparisons. Outcomes were reported at six months to three years post transplant. Risk of bias was judged to be low for sequence generation in 25 studies, for allocation concealment in 23 studies, performance bias in four studies, detection bias in 65 studies, attrition bias in 45 studies, selective reporting bias in 48 studies, and for other potential bias in three studies. Risk of bias was judged to be at high risk of bias for sequence generation in two studies, allocation concealment in two studies, performance bias in 61 studies, detection bias in one study, attrition bias in four studies, for selective reporting bias in 11 studies and for other potential risk of bias in 46 studies. Compared with CNI and antimetabolite, TOR‐I with antimetabolite probably makes little or no difference to death (RR 1.31, 95% CI 0.87 to 1.98; 19 studies) or malignancies (RR 0.86, 95% CI 0.50 to 1.48; 10 studies); probably increases graft loss censored for death (RR 1.32, 95% CI 0.96 to 1.81; 15 studies), biopsy‐proven acute rejection (RR 1.60, 95% CI 1.25 to 2.04; 15 studies), need to change treatment (RR 2.42, 95% CI 1.88 to 3.11; 14 studies) and wound complications (RR 2.56, 95% CI 1.94 to 3.36; 12 studies) (moderate certainty evidence); but reduces CMV infection (RR 0.43, 95% CI 0.29 to 0.63; 13 studies) (high certainty evidence). Compared with antimetabolites and CNI, TOR‐I with CNI probably makes little or no difference to death (RR 1.06, 95% CI 0.84 to 1.33; 31 studies), graft loss censored for death (RR 1.09, 95% CI 0.82 to 1.45; 26 studies), biopsy‐proven acute rejection (RR 0.95, 95% CI 0.81 to 1.12; 24 studies); and malignancies (RR 0.83, 95% CI 0.64 to 1.07; 17 studies); probably increases the need to change treatment (RR 1.56, 95% CI 1.28 to 1.90; 25 studies), and wound complications (RR 1.56, 95% CI 1.28 to 1.91; 17 studies); but probably reduces CMV infection (RR 0.44, 95% CI 0.34 to 0.58; 25 studies) (moderate certainty evidence). Lower dose TOR‐I and standard dose CNI compared with higher dose TOR‐I and reduced dose CNI probably makes little or no difference to death (RR 1.07, 95% CI 0.64 to 1.78; 9 studies), graft loss censored for death (RR 1.09, 95% CI 0.54 to 2.20; 8 studies), biopsy‐proven acute rejection (RR 0.87, 95% CI 0.67 to 1.13; 8 studies), and CMV infection (RR 1.42, 95% CI 0.78 to 2.60; 5 studies) (moderate certainty evidence); and may make little or no difference to wound complications (RR 0.95, 95% CI 0.53 to 1.71; 3 studies), malignancies (RR 1.04, 95% CI 0.36 to 3.04; 7 studies), and the need to change treatments (RR 1.18, 95% CI 0.58 to 2.42; 5 studies) (low certainty evidence). Lower dose of TOR‐I compared with higher doses probably makes little or no difference to death (RR 0.84, 95% CI 0.67 to 1.06; 13 studies), graft loss censored for death (RR 0.92, 95% CI 0.71 to 1.19; 12 studies), biopsy‐proven acute rejection (RR 1.26, 95% CI 1.10 to 1.43; 11 studies), CMV infection (RR 0.87, 95% CI 0.63 to 1.21; 9 studies), wound complications (RR 0.92, 95% CI 0.66 to 1.29; 7 studies), and malignancy (RR 0.84, 95% CI 0.54 to 1.32; 10 studies) (moderate certainty evidence); and may make little or no difference to the need to change treatments (RR 0.91, 95% CI 0.78 to 1.05; 10 studies) (low certainty evidence). It is uncertain whether sirolimus and everolimus differ in their effects on kidney function and lipid levels because the certainty of the evidence is very low based on a single small study with only three months of follow‐up. Authors' conclusions In studies with follow‐up to three years, TOR‐I with an antimetabolite increases the risk of graft loss and acute rejection compared with CNI and an antimetabolite. TOR‐I with CNI potentially offers an alternative to an antimetabolite with CNI as rates of graft loss and acute rejection are similar between interventions and TOR‐I regimens are associated with a reduced risk of CMV infections. Wound complications and the need to change immunosuppressive medications are higher with TOR‐I regimens. While further new studies are not required, longer‐term follow‐up data from participants in existing methodologically robust RCTs are needed to determine how useful immunosuppressive regimens, which include TOR‐I, are in maintaining kidney transplant function and survival beyond three years

Resultados clínicos en receptores de trasplante renal posterior a la conversión a ImTOR

Introducción: los ImTOR, sirolimus y everolimus son una alternativa de inmunosupresión en personas que han recibido transplantes rena-les. En este artículo, se describe la experiencia de pacientes que han experimentado una conversión a ImTOR, y a los que se les ha hecho un seguimiento por más de cinco años.Materiales y métodos: se incluyeron pacientes con transplantes renales desde 1995 hasta 2013, quienes tuvieron indicación de suspensión del inhibidor de calcineurina (ICN) después del tercer mes posterior al trasplante. Todos los pacientes fueron sometidos a biopsia renal antes de la administración de ImTOR. Ningún paciente tuvo diagnóstico de nefropatía crónica, IFTA >40 % o proteinuria >350 mg/24h. Se elaboró un análisis descriptivo para todas las variables. Para estudiar la supervivencia del paciente y del injerto, y la incidencia de rechazo agudo, se usó el método de Kaplan-Meier.Resultados: de 1273 trasplantes renales, la conversión de ICN a ImTOR se realizó en 166 casos (13 %). Al 78 % (n=129) se le administró sirolimus. El 13 % de los pacientes perdió la función del injerto y 7 pacientes (4,2 %) fallecieron. En el 37 % de los casos, se retiró el ImTOR. La principal causa de retiro fue el hallazgo de proteinuria patológica. La incidencia de rechazo agudo después del cambio a ImTOR fue de 9,6 %. La supervivencia del injerto tras uno y cinco años fue de 96,6 % y 83,5 %, respectivamente; y la supervivencia del paciente a uno y cinco años fue de 98 % y 97 %, respectivamente.Conclusiones: el uso de inhibidores ImTOR parece ser seguro en este grupo de pacientes trasplantados, pues hubo una baja tasa de rechazo y buena supervivencia del injert