Interleukin-9 in stable liver transplant recipients

Introduction

Interleukin-9 (IL-9) has recently been described to be involved in the maintenance of a tolerant environment, but there is no evidence of its role in human liver transplantation. The aim of our study was to measure the serum levels of IL-9 in stable liver transplant recipients and examine their influence on immunosuppressant load.

Methods

Serum IL-9 levels were determined in 34 healthy subjects and 30 stable liver transplant recipients who were free of rejection episodes for at least 8 years. The results were analyzed according to the blood levels of calcineurin inhibitors (CNIs) at the time of the study: 13 patients showed high concentrations of either cyclosporine or tacrolimus (high CNI: cyclosporine > 80 ng/mL or tacrolimus > 5 ng/mL) and another 17 patients showed low CNI levels.

Results

The concentrations of IL-9 were significantly higher among liver transplant recipients compared with healthy subjects. In addition, patients with low CNI blood levels showed higher serum levels of IL-9, an effect that was greater with tacrolimus, albeit not significantly.

Conclusions

These preliminary results indicated that increased serum IL-9 concentrations accompanied a lower immunosuppressive load. It remains to be established whether this relates to induction of tolerance in liver transplantation.     

A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice

Background

The identification by CFTR mRNA studies of a new deep-intronic splicing mutation, c.870-1113_1110delGAAT, in one patient of our series with mild CF symptoms and in three CF patients of an Italian study, led us to evaluate the mutation frequency and phenotype/genotype correlations.

Methods

266 patients with CF and related disorders and having at least one undetected mutation, were tested at the gDNA level in three French reference laboratories.

Results

In total, the mutation was found in 13 unrelated patients (5% of those already carrying a mutation) plus 4 siblings, including one homozygote and 12 heterozygotes having a severe CF mutation. The sweat test was positive in 10/14 documented cases, the diagnosis was delayed after 20 years in 9/15 and pancreatic insufficiency was present in 5/16.

Conclusion

c.870-1113_1110delGAAT should be considered as CF-causing with phenotype variability and overall delayed diagnosis. Its frequency highlights the potential of mRNA studies.     

Suitable calcineurin inhibitor concentrations for liver transplant recipients in the Chinese population

Aim

The aim was to deduce suitable calcineurin inhibitor concentrations for the Chinese liver transplantation population.

Methods

We retrospectively studied 97 liver transplant recipients who displayed stable liver and renal function. No grafts were obtained from prisoners, procurements were performed with donor consent conforming to international ethics regulations. At 3, 6, and 12 months, we increased the concentrations and doses of calcineurin inhibitors as well as the values of alanine transaminase and serum creatinine.

Results

Twenty-eight recipients received cyclosporine and 69 tacrolimus. The mean cyclosporine daily dosages were 203 ± 62 mg at 3, 188 ± 55 mg at 6, and 173 ± 52 mg at 12 months, the tacrolimus daily dosages were 3.08 ± 0.98, 2.82 ± 0.98, and 2.58 ± 0.93 mg, respectively. The corresponding mean cyclosporine peak concentrations (C₂) were 806 ± 322 ng/mL, 681 ± 206 ng/mL, and 644 ± 190 ng/mL and the mean tacrolimus trought concentrations (C₀) 6.61 ± 3.02 ng/mL, 5.85 ± 2.44 ng/mL, and 5.22 ± 2.33 ng/mL, respectively. In both groups, transaminases and serum creatinine were stable over time.

Conclusions

An individualized immunosuppressive regimen for the local population is necessary. We delayed calcineurin inhibitors with subsequent low-dose mycophenolate mofetil plus minimized calcineurin inhibitors, which seemed to be nephropreotective and safe for Chinese liver transplantation patients.     

Cost-effectiveness analysis of the early conversion of tacrolimus to mammalian target of rapamycin inhibitors in patients with renal transplantation

Background

Renal replacement therapies which consist of renal transplantation and dialysis are the only treatment options for patients with terminal renal failure. These therapies have changed the outcome from being fatal to being a chronic disease. Kidney transplantation involves the use of immunosuppressive agents to prevent rejection. Currently, several immunosuppressive agents have shown efficacy, safety, and different costs.

Objective

The aim was to evaluate the cost-effectiveness of early conversion from tacrolimus to mammalian target of rapamycin inhibitors sirolimus or everolimus versus continuous treatment with tacrolimus among renal transplantat patients in Colombia.

Methods

We performed systematic literature review to extract data for clinical effectiveness and safety of tacrolimus replacement schemes for immunosuppressive therapy in renal transplantation in adults. A Markov model in TreeAge was developed, simulating the patient's natural history with renal transplantation. The perspective of the Colombian Health System was used, including only direct costs. The cost-effectiveness ratio and incremental cost-effectiveness ratio were estimated. Deterministic and probabilistic sensitivity analyses were performed. A 5% discount rate was applied in costs and health results.

Results

Results for the replacement of tacrolimus to sirolimus are provided. The cost per year of additional life gained for sirolimus was Col$2,441,171.43; the cost for avoided loss was Col$4,014,152.84. The acceptability curve shows that a strategy with sirolimus is the most cost-effective one.

Conclusions

This study suggested that the sirolimus strategy is cost-effective in Colombia for patients with renal transplantation using as threshold less than three times the gross domestic product (GDP) per capita of Colombia per life of years gained.     

Effect of Immunosuppressant Blood Levels on Serum Concentration of Interleukin-17 and -23 in Stable Liver Transplant Recipients

Introduction

T_H17 cells have been recently described to be involved in inflammatory and immune-mediated diseases, but there is no evidence of their role in human liver transplantation. Interleukin (IL)-23 is considered an inducer cytokine, whereas IL-17 is the main cytokine released by T_H17 cells. The aim of our study was to measure the serum levels of IL-17 and IL-23 in stable liver transplant recipients and examine the influence of immunosuppressant concentrations.

Materials and Methods

Serum levels of IL-23 and IL-17 were determined in 38 healthy subjects and 35 stable hepatic transplant recipients who were free of rejection episodes for at least 8 years. The results were analyzed according to the simultaneous blood levels of cyclosporine (n = 20) or tacrolimus (n = 15).

Results

No significant differences were observed in the serum levels of IL-17 and IL-23 between healthy subjects and transplanted patients. In addition, patients with low blood levels of tacrolimus (<6 ng/mL), but not cyclosporine, showed significantly lower serum levels of the 2 cytokines.

Conclusion

These preliminary results suggested a lack of activation of the T_H17 pathway, which was more pronounced among the patient subgroup treated with tacrolimus.     

Effects of tacrolimus on antioxidant status and oxidative stress in glioma cells

Objectives

After organ transplantation, some patients suffer from mild neurologic symptoms, ranging from tremor to severe complications, including seizures and encephalopathy. Among the immunosuppressants, tacrolimus can cause neurologic side effects. However, the mechanisms of encephalopathy by tacrolimus are not fully understood. We measured the antioxidant status, hydrogen peroxide level, and malondialdehyde level in glioma cells after tacrolimus treatment.

Methods

The production of hydrogen peroxide was determined by the modified xylenol orange method. The amount of malondialdehyde was measured by the thiobarbituric acid assay, which is based on malondialdehyde reaction with thiobarbituric acid to give a red species absorbing at 535 nm. Total antioxidant status (TAS) was measured using TAS kits (NX2332).

Results

Tacrolimus resulted in dose- and time-dependent increases in the production of hydrogen peroxide by glioma cells. The antioxidant status decreased in the glioma cells after tacrolimus treatment. Malondialdehyde level was unchanged in the glioma cells after tacrolimus treatment.

Conclusions

Increased production of reactive oxygen species and decreased antioxidant status by tacrolimus in glioma cells may contribute to neurologic side effects.     

Supplementation of retrobulbar block with clonidine in vitreoretinal surgery: effect on postoperative pain

Study Objective

To evaluate the effect of clonidine when added to local anesthetics on duration of postoperative analgesia during retrobulbar block.

Design

Prospective, randomized controlled trial.

Setting

Operating room and Postanesthesia Care Unit of a university-affiliated hospital.

Subjects

80 ASA physical status 1, 2, and 3 patients undergoing vitreoretinal surgery with or without scleral buckling.

Interventions

Patients in the control group (n = 40) received a retrobulbar block with 4.5 mL of lidocaine-bupivacaine and 0.5 mL of saline. Clonidine group patients (n = 40) received 4.5 mL of lidocaine-bupivacaine and 0.5 μg/kg of clonidine in a 0.5 mL volume.

Measurements

The time to first analgesic request, frequency of postoperative pain, and number of postoperative analgesic requests per patient were assessed.

Main Results

37 patients in the control group (92.5%) versus 24 patients (60%) in the clonidine group reported pain postoperatively (P = 0.001), with a shorter time to first analgesic request noted in the control group (4.9 ± 3 vs 11.9 ± 5.3 hrs; P < 0.001). The median number of postoperative analgesic requests per patient during the first 24 hours was higher in the control group than the clonidine group [2 (0-3) vs. 1 (0-3); P < 0.001].

Conclusions

The addition of clonidine 0.5 μg/kg to the local anesthetics of a retrobulbar block for vitreoretinal surgery decreases the frequency of postoperative pain and prolongs the time of analgesia.     

The production of reactive oxygen species in tacrolimus-treated glial cells

Objective

After organ transplantation, some patients suffer from mild neurological symptoms, such as tremor, to severe complications, including seizures and encephalopathy. These neurological side effects can be caused by immunosuppressants such as tacrolimus. However, the mechanism of encephalopathy by tacrolimus is not fully understood.

Methods

We measured the production of reactive oxygen species (ROS) in glioma cells after tacrolimus treatment. Tacrolimus added to glioma cells was incubated for 60 minutes at 37°C. The production of ROS was evaluated by measuring the fluorescent product from the oxidation of an oxidant-sensitive 2′,7′-dichlorofluorescin using VICTOR^3TM multilabel counter.

Results

Tacrolimus resulted in the production of the ROS in glioma cells. The production of the ROS was increased in time-dependent fashion.

Conclusions

These findings indicated that the tacrolimus may contribute the neurological side effects by ROS production.     

Renal transplantation in patients with human T-cell lymphotropic virus type 1

Background

Renal transplantation (RTx) in carriers of human T-cell lymphotropic virus type 1 (HTLV-1) has a risk of developing overt leukemia upon immunosuppression. Although there have been a few reports of such cases, it is unclear HTLV-1 carrier if patients on the modern immunosuppressants would develop HTLV-1-associated myelopathy or adult T-cell leukemia lymphoma.

Methods

We retrospectively reviewed the clinical outcomes of RTx in nine HTLV-1 carriers to assess a risk of developing leukemia from 2002 to 2011 using immunosuppression with a calcineurin inhibitor, mycophenolate mofetil (MMF), and steroid. The anti-CD25 monoclonal antibody basiliximab was used for induction. In two cases of ABO-incompatible RTx, the rituximab was also administered before RTx.

Results

The ratio of male to female subjects was 2 to 7 with an overall mean recipient age of 54.3 ± 8.1 years. We prescribed cyclosporine (n = 5) or tacrolimus (n = 4). There was only one graft loss due to the death caused by aspiration pneumonia with a functioning graft. No one developed overt leukemia with combined treatment with MMF, basiliximab and rituximab.

Conclusion

We concluded that RTx in HTLV-1 carriers could be performed using a modern immunosuppressive regimen, without the risk of developing leukemia.     

Cytokine Profile in Pleural Fluid and Serum After Lung Transplantation

Background

Lung transplantation is the procedure of choice in several end-stage lung diseases. Despite improvements in surgical techniques and immunosuppression, early postoperative complications occur frequently.

Objective

To evaluate the pleural inflammatory response after surgery.

Patients and Methods

Twenty patients aged 18 to 63 years underwent unilateral or bilateral lung transplantation between August 2006 and March 2008. Proinflammatory cytokines interleukin (IL)-1β, IL-6, and IL-8 and vascular endothelial growth factor in pleural fluid and serum were analyzed. For cytokine evaluation, 20-mL samples of pleural fluid and blood (right, left, or both chest cavities) were obtained at 6 hours after surgery and daily until removal of the chest tube or for a maximum of 10 days. Data were analyzed using analysis of variance followed by the Holm-Sidak test.

Results

All effusions were exudates according to Light's criteria. Pleural fluid cytokine concentrations were highest at 6 hours after surgery. Serum concentrations were lower than those in pleural fluid, and IL-1β, IL-6, and IL-8 were undetectable at all time points.

Conclusions

There is a peak concentration of inflammatory cytokines in the first 6 hours after transplantation, probably reflecting the effects of surgical manipulation. The decrease observed from postoperative day 1 and thereafter suggests the action of the immunosuppression agents and a temporal reduction in pleural inflammation.     

Prospective Study of Switch From Cyclosporine to Tacrolimus for Fibroadenomas of the Breast in Kidney Transplantation

Introduction

Breast fibroadenomas may result from exposure to cyclosporine (CsA). The aim of this prospective study was to assess the reversibility of breast fibroadenomas following conversion from CsA to tacrolimus among a small cohort of female renal transplant recipients.

Methods

Following renal transplantation, fibroadenomas either developed or progressed in eight Caucasian female patients with CsA-based immunosuppression. These patients were enrolled in a pilot study assessing whether conversion from a CsA-based to a tacrolimus-based regimen prevented progression of breast disease or reversed existing lumps. Patients underwent a baseline visit in which we assessed the clinical history, number and dimension of fibroadenomas, graft function and hormonal profile (FSH prolactin, estradiol and progesterone). Twenty-one lumps were described in six patients; in addition, two patients had “grapes of fibroadenomas,” of nondefinable numbers.

Results

Patients underwent conversion to tacrolimus after a mean of 63.8 ± 37.4 months after renal transplantation. Of the 21 clearly described lumps complete reversibility was observed for eight fibroadenomas. Other fibroadenomas either decreased in size or remained stable without further progression. These changes were reported within 1 year following conversion to tacrolimus.

Conclusion

A switch from CsA to tacrolimus was effective to prevent the progression of fibroadenomas. In female renal transplant recipients with CsA-based immunosuppression suffering from breast fibroadenomas, early CsA withdrawal may avoid the need for breast surgery.     

A 6-Month, Multicenter, Single-Arm Pilot Study to Evaluate the Efficacy and Safety of Generic Tacrolimus (TacroBell) After Primary Renal Transplantation

Objective

Tacrolimus has been shown to be an important immunosuppressive agent in organ and bone marrow transplantation. Previously, we reported that there were no statistically significant differences between the pharmacokinetic parameters of the oral formulation of generic tacrolimus (TacroBell) and the conventional formulation (Prograf). This study was designed to evaluate the efficacy and safety of oral capsules of TacroBell in de novo renal transplantation.

Methods

Ninety-six renal transplant recipients from 9 transplantation centers in South Korea were enrolled between November 2005 and July 2007. De novo renal recipients ranged from 19-65 years old. Ninety-four patients who underwent renal transplantation were administered study drug at least one time in the intent-to-treat (ITT) analysis. This phase 4 clinical trial was a 26-week, open-label, noncomparative, multicenter study.

Results

An acute rejection episode developed in 10/94 recipients (10.6%, 95% confidence interval, 4.4%-16.9%). There were no patient deaths during the study. The 6-month graft survival rate was 96.8%.

Conclusion

Based on this study, treatment with TacroBell is considered to be efficient and safe after primary renal transplantation.     

The excellent outcomes of ABO-incompatible kidney transplantation with high titer (>×2048) using anti-CD20 and anti-CD25 antibody without splenectomy: two case reports

Background

Due to the shortage of deceased donors, we have expanded the indications for living-donor kidney transplantation (LKT) to include ABO-incompatible (ABO-i) individuals. However, which patients with high-titer anti-blood-group antibody can be transplanted successfully is unclear.

Methods

Since 2009 we have performed 2 high-titer ABO-i spousal LKT using anti-CD20 and anti-CD25 monoclonal antibody without splenectomy. In both cases, anti-type A antibody was 2048-fold before antibody removal. The immunosuppressive regimen consisted of 2 doses of anti-CD20 antibody (200 mg/body, day -14 to day -7), mycophenolate mofetil (1000 mg), prednisolone (10 mg starting from day -14), calcineurin inhibitor (cyclosporine [7 mg/kg] or tacrolimus [0.2 mg/kg] starting from day -7), and 2 doses of anti-CD25 antibody (20 mg/body, days 0 and 4). Antibody removal by plasmapheresis was performed up to 4 times before LKT according to the antibody titer. The posttransplantation regimen consisted of mycophenolate mofetil or mizoribine as antimetabolite. A protocol biopsy was performed at 1 month and 1 year after LKT.

Result

The 60- and 62-year-old men had renal graft transplantation performed in the right hemipelvis without complication. After LKT, urinary output and serum creatinine decrease were within acceptable ranges without evidence of an acute rejection episode for 12 and 7 months, respectively. Patient and graft survival rates were 100%. A protocol biopsy at 1 month after LKT showed additional treatment to be unnecessary. Serious viral infection was not seen, even in the 1 patient who temporarily experienced positive changes in cytomegalovirus antigenemia.

Conclusions

We obtained good clinical results among 2 high-titer ABO-i LKT using anti-CD20 and anti-CD25 antibodies without splenectomy, in conjunction with a calcineurin inhibitor plus mycophenolate mofetil or mizoribine.     

The 4-week serum creatinine level predicts long-term renal dysfunction after adult living donor liver transplantation

Objectives

Recipients after liver transplantation. (OLT) often experience renal dysfunction. Acute kidney injury (AKI) and chronic kidney disease (CKD) after OLT occur among 20% to 50% and 30% to 90% of recipients, respectively; 2% to 5% of them deteriorate into end-stage renal disease each year. Since the predictable factors for CKD have not been well identified. We sought to investigate the incidence and predictors of CKD at 5 years after OLT.

Patients and methods

Between August 2002 and December 2005, we enrolled 77 patients who underwent adult living donor OLT with over 2 years of follow-up. The strategies to prevent renal dysfunction included induction with basiliximab to delay the use of tacrolimus: addition of mycophenolate mofetil to reduce the tacrolimus dosage; avoidance of the calcineurin inhibitor using sirolimus or administration of an angiotensin II receptor antagonist. The clinical variables were reviewed for analysis.

Results

The mean follow-up was 76 ± 14 months. The incidence of AKI (over 50% increase level of creatinine) was 29%. Ten (13.0%) patients developed CKD (creatinine > 2 mg/dL). One (1.3%) subject developed end-stage renal disease requiring hemodialysis. Upon multivariate analysis the development of CKD was significantly associated with the posttransplant 4-week creatinine level: 0.92 ± 0.23 versus 1.37 ± 0.93 mg/dL (P = .008).

Conclusion

The 4-week creatinine value was predictive of the occurence of CKD over 5 years after OLT.     

Early Expression of Hepatocyte Growth Factor, Interleukin-6, and Transforming Growth Factor-β1 and -β2 in Symptomatic Infection in Patients Who Have Undergone Liver Transplantation

Introduction

Early septic complications may be a deciding factor for successful recovery among patients who have undergone orthotopic liver transplantation. Therefore, monitoring liver function parameters plays an important role in postoperative treatment to achieve an early diagnosis of postsurgical complications. We ought to measure standard liver function parameters and the expression levels for selected cytokines among patients exhibiting symptoms of infection after orthotopic liver transplantation.

Materials and methods

The study was performed on 30 patients who were divided into two groups: SI-0 consisted of patients free of infection, and SI-1, those who had symptoms of infection. We determined standard liver function parameters and expression of hepatocyte growth factor (HGF), interleukin (IL)-6, transforming growth factor (TGF)-β1, and TGF-β2.

Results

There were no significant differences in standard liver function parameters between the two groups of patients. There were no significant differences in the levels of expression for the cytokines in question between the two groups of patients.

Conclusions

Although standard liver function parameters provide diagnostically valuable information on the patient's condition, they cannot be used to determine the extent of systemic infection among patients showing signs of infection after liver transplantation. Determining gene expression levels in circulating lymphocytes is a sensitive method to monitor patients' condition after liver transplantation. The expression levels of HGF, IL-6, TGF-β1, and TGF-β2 in circulating lymphocytes were not sufficiently specific to diagnose transitory postsurgical complications such as symptomatic infection.     

The impact on biochemical profiles and allograft function for patients converted from cyclosporine to tacrolimus after clinical heart transplantation

Objective

Tacrolimus, a potent calcineurin inhibitor, is a widely used immunosuppressant. This study sought to determine whether conversion from cyclosporine to tacrolimus afforded benefits on biochemical profiles and graft function among Chinese heart transplantation recipients.

Methods

Forty-nine patients (44 men and 5 women) among 252 heart transplantations performed from 1995 to 2005 were converted from cyclosporine to tacrolimus due to rejection (69%) or to cyclosporine intolerance (31%). The median age of these recipients at transplantation was 46.4 years (range, 5 months to 68 years). Their median body weight was 60 kg (range, 4-84 kg). The allograft median ischemic time was 145 minutes (range, 52-300 minutes). We compared the biochemical markers, rejection episodes and allograft function.

Results

The mean duration from heart transplantation to conversion was 419 days. After conversion, the serum bilirubin and alanine transaminase levels were significantly improved at 1 year. The lipid profiles, including triglycerides, total cholesterol, and low-density lipoprotein were nonsignificantly changed. The rejection episodes significantly decreased from 1.53 to 0.15 per patient per year (P < .001). The left ventricular ejection fraction significantly improved from 54.3 ± 17.9% to 63.2 ± 10.9% (P < .01). The right atrial pressure significantly decreased from 9.1 ± 5.8 mmHg to 6.3 ± 4.3 mm Hg (P < .01). The pulmonary capillary wedge pressure significantly decreased from 15.3 ± 9.5 mm Hg to 10.8 ± 5.3 mm Hg (P = .04).

Conclusion

In heart transplantation, conversion to tacrolimus owing to rejection or cyclosporine intolerance showed better liver profiles with fewer rejection episodes and improved graft function.     

Glucocorticoid treatment down-regulates chemokine expression of bacterial cholangitis in cholestatic rats

Background

Postoperative cholangitis is common after operation for biliary atresia. Empirical pulse therapy with glucocorticoid is effective in reversing some detrimental clinical manifestations, but the rationale for such a therapy still is not substantiated.

Methods

Adult male rats were divided into groups according to the treatment: sterile normal saline (NS) or Escherichia coli (EC, 1 mL containing 10⁸ cells of ATCC 25922 strain), 1 mL, were infused into the proximal choledochostomy (PC) tube 2 weeks after ligation of the PC tube (bile duct ligation, BDL), then immediate tube-tube choledocho-choledochostomy (biliary drainage, BD) was constructed. A high dose of dexamethasone (DEX, intraperitoneal injection; 2 mg/kg of body weight) was given after BD in treatment groups. Histopathology of the liver, as well as liver chemokine mRNA expression and serum chemokine levels, were studied 24 hours after treatment.

Results

Inflammatory cell infiltration to the liver was retarded with DEX treatment, which was correlated with a significantly lower expression of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) mRNA in the liver (P = .006). Serum IL-8 and MCP-1 levels were also significantly down-regulated with DEX treatment (P = 0.008).

Conclusions

Glucocorticoid treatment is effective in modulating IL-8 and MCP-1 expression and ameliorating inflammatory cell infiltration in rat liver with bacterial cholangitis and cholestasis.