Prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation

OBJECTIVE: Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation. METHODS: Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups. RESULTS: Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01). CONCLUSION: The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.

Effects of immunosuppression with tacrolimus and mycophenolate mofetil on renal histology and function in single kidney rats submitted to ischemia and reperfusion

PURPOSE: To evaluate renal histological changes and renal function in single kidney rats submitted to renal ischemia-reperfusion and to immunosuppression with tacrolimus and mycophenolate-mofetil. METHODS: Experimental study with 80 Wistar rats distributed into control, Sham and six other groups treated with immunosuppressive drugs. Animals undergoing surgery, right nephrectomy and left renal clamping, killed on the 14th day and analyzed for renal histology, urea and creatinine. RESULTS: The group receiving tacrolimus at higher doses (T3) showed renal histological lesions indicative of early nephrotoxicity, and significant increase in urea and creatinine. The group M (mycophenolate-mofetil alone) and the group M2 (mycophenolate-mofetil combined with half the usual dose of tacrolimus) presented a slight rise in serum urea. The groups using mycophenolate-mofetil alone or combined with tacrolimus showed creatinine levels similar to that of the group T3. CONCLUSIONS: Histologically, the association of injury by ischemia-reperfusion with the use of tacrolimus or mycophenolate-mofetil alone demonstrated a higher rate of renal changes typical of early nephrotoxicity. In laboratory, the combination of injury by ischemia-reperfusion with tacrolimus at higher doses proved to be nephrotoxic. .

An analysis of tacrolimus-related complications in the first 30 days after liver transplantation

OBJECTIVES: Orthotopic liver transplantation has improved survival in patients with end-stage liver disease; however, therapeutic strategies that achieve ideal immunosuppression and avoid early complications are lacking. To correlate the dose and level of Tacrolimus with early complications, e.g., rejection, infection and renal impairment, after liver transplantation. From November 2011 to May 2013, 44 adult liver transplant recipients were studied in this retrospective comparative study. RESULTS: The most frequent indication for liver transplantation was hepatitis C cirrhosis (47.7%), with a higher prevalence observed in male patients (68.18%). The ages of the subjects ranged from 19-71 and the median age was 55.5 years. The mean length of the hospital stay was 16.1±9.32 days and the mean Model for End-stage Liver Disease score was 26.18±4.28. There were five cases of acute cellular rejection (11.37%) and 16 cases of infection (36.37%). The blood samples that were collected and analyzed over time showed a significant correlation between the Tacrolimus blood level and the deterioration of glomerular filtration rate and serum creatinine (p<0.05). Patients with infections had a higher serum level of Tacrolimus (p = 0.012). The dose and presence of rejection were significantly different (p = 0.048) and the mean glomerular filtration rate was impaired in patients who underwent rejection compared with patients who did not undergo rejection (p = 0.0084). CONCLUSION: Blood Tacrolimus levels greater than 10 ng/ml were correlated with impaired renal function. Doses greater than 0.15 mg/kg/day were associated with the prevention of acute cellular rejection but predisposed patients to infectious disease. .

Performance Evaluation of Affinity Column Mediated Immunometric Assay for Tacrolimus / 대한진단검사의학회지

BACKGROUND: Therapeutic drug monitoring (TDM) of tacrolimus is essential because of narrow therapeutic range and poor correlation of dose to blood concentration. Affinity Column Mediated Immunometric Assay (ACMIA) does not require a pretreatment steps in measurement of tacrolimus. In this study, we evaluated the performance of tacrolimus assay using ACMIA (Dimension RxL Max, Dade Behring). METHODS: The imprecision, the linearity and the detection limits and the interferences by bilirubin and chyle, and correlation with hematocrit for tacrolimus by ACMIA were evaluated according to Clinical and Laboratory Standards Institute guidelines EP5-A2, EP6-A, EP17-A, EP9-A2, and EP7-A2. Method comparison studies with microparticle enzyme immunoassay (MEIA) (IMx Tacrolimus II, Abbott Laboratories) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) (Waters 2795 Quattromicro API, Micromass) were also performed. RESULTS: The total imprecision for low, middle and high level was 12.8%, 9.0% and 6.7%, respectively. The range of tacrolimus from 3.1 ng/mL to 35.4 ng/mL showed a clinically relevant linearity. The limit of detection and the functional sensitivity were 0.24 ng/mL and 0.72 ng/mL, respectively. Tacrolimus concentration measurement (Tac-CM) with ACMIA did not show significant interferences with bile and chyle and also did not show significant correlation with hematocrit. In comparison study for Tac-CM with MEIA and LC-MS/MS, Tac-CM with ACMIA showed a good correlation with MEIA (r=0.950) and LC-MS/MS (r=0.946). CONCLUSIONS: The imprecision, linearity, detection limits, interference and correlation of Tac-CM with ACMIA were suitable for clinical use. Tac-CM with ACMIA could reduce turn around time and help clinicians to manage transplant patients on immunosuppressant therapy.

Therapeutic drug monitoring of tacrolimus in pancreas transplantation at São Lucas Hospital

Tacrolimus (FK 506), a potent immunosuppressive drug used in prevention and treatment of rejection of transplanted organs, exhibits efficacy related to its blood levels and has a narrow therapeutic index. These factors require frequent monitoring of patients blood levels, in attempt to adjust the dose to reach the best drug concentration with minimum side effects. In this historic study, the authors evaluated tacrolimus blood profile in patients submitted to pancreas transplantation between June 2002 and March 2004. The results show that blood levels were, mostly, within subtherapeutic (39.1 percent) and toxic (43.4 percent) ranges. Considering post-transplantation period, subtherapeutic levels were more frequent until three months after the graft receiving (51.1 percent) and between three and six months (41.9 percent), whereas toxic levels were more common six months after the transplantation (63 percent). Patients who received pancreas/kidney transplantation showed a tendency to present toxic levels. The same did not happen with the patients who received isolated pancreas and pancreas after kidney; these patients presented subtherapeutic blood levels in all post-transplantation periods. The results found in this study reassure the importance of therapeutic monitoring to achieve the adequate blood levels of tacrolimus following pancreas transplantation.

O tacrolimus (FK506), um potente imunossupressor utilizado na profilaxia e no tratamento de rejeições pós-transplante, exibe eficácia relacionada com sua concentração sangüínea e possui estreita janela terapêutica. Esses fatores requerem o freqüente monitoramento dos níveis sangüíneos em pacientes que fazem uso do fármaco, tendo como objetivo o ajuste de dose para uma concentração terapêutica ótima com efeitos colaterais mínimos. Este estudo retrospectivo foi realizado através do acesso à base de dados do Laboratório de Patologia Clínica do Hospital São Lucas, da Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), e teve por objetivo analisar o perfil das concentrações sanguíneas de tacrolimus em pacientes transplantados de pâncreas, no período de junho de 2002 a março de 2004. Os resultados mostram que as concentrações se encontravam, em sua maioria, em níveis subterapêuticos (39,1 por cento) e tóxicos (43,4 por cento). Considerando-se o período pós-transplante, níveis subterapêuticos foram mais freqüentes nos períodos de zero a três meses (51,1 por cento) e de três a seis meses (41,9 por cento) após o transplante, enquanto níveis tóxicos (63 por cento) foram mais freqüentes após seis meses. Pacientes que receberam pâncreas/rim simultâneo apresentaram, de maneira geral, mais concentrações em níveis tóxicos; o mesmo não aconteceu em pacientes que receberam pâncreas isolado e pâncreas pós-rim. Os pacientes que receberam pâncreas isolado e pâncreas pós-rim tenderam a apresentar níveis subterapêuticos em todos os períodos pós-transplante considerados. Os resultados obtidos neste trabalho demonstram a importância do monitoramento terapêutico, uma vez que seus resultados orientam o ajuste das doses.