Vivian C. McAlister

Sirolimus-tacrolimus combination immunosuppression

A series of 32 recipients of liver, kidney, or pancreas transplants who were treated with sirolimus and low-dose tacrolimus experienced a low rate of rejection and excellent graft function without drug-related toxic effects.

Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation

Patients undergoing orthotopic liver transplantation (OLT) have excessive blood loss during surgery that requires blood transfusions, leading to increased postoperative morbidity and mortality. We studied the efficacy and safety of activated recombinant factor VII (rFVIIa) in reducing transfusion requirements in OLT. This multicenter, randomized, double‐blind, placebo‐controlled trial enrolled patients undergoing OLT because of cirrhosis (Child‐Turcotte‐Pugh class B or C). Patients received a repeated intravenous bolus regimen of rFVIIa 60 or 120 μg/kg or placebo. The primary efficacy endpoint was the total number of red blood cell (RBC) units transfused during the perioperative period. A total of 182 patients were analyzed for efficacy and 183 for safety. No significant effect of rFVIIa was observed on the number of RBC units transfused or intraoperative blood loss compared with the placebo group. A significantly higher number of patients in the rFVIIa study groups avoided RBC transfusion. Administration of rFVIIa but not placebo restored the preoperative prolonged prothrombin time to normal value during surgery. Patients receiving rFVIIa and placebo did not experience a significant difference in rate of thromboembolic events. Additionally, there was no statistically significant effect of rFVIIa treatment on hospitalization rate, total surgery time, and the proportion of patients undergoing retransplantation. In conclusion, use of rFVIIa during OLT significantly reduced the number of patients requiring RBC transfusion. There was no increase in thromboembolic events with rFVIIa administration compared with placebo. (Liver Transpl 2005;11:973–979.)

Metabolic syndrome in liver transplant recipients: Prevalence and association with major vascular events

Cardiac and cerebral vascular diseases are leading causes of morbidity and death in solid organ transplant recipients. Immunosuppressant drugs are associated with dyslipidemia, hypertension, and hyperglycemia, which along with obesity are the main features of metabolic syndrome. In the nontransplant population, metabolic syndrome is associated with increased risk for major vascular complications. We postulated that metabolic syndrome is common post–liver transplantation and plays a significant role leading to cardiac and cerebrovascular events. Our Multi‐Organ Transplant Program database was reviewed for all liver transplant recipients between January 1998 and June 2004 with follow‐up until December 2005. We adapted the 2001 National Cholesterol Education Program‐Adult Treatment Panel III Guidelines to define posttransplantation metabolic syndrome (PTMS) as the presence at least 3 of the following: 1) obesity (body mass index >30 kg/m2); 2) serum triglyceride level ≥1.7 mmol/L; 3) high density lipoprotein level <1 mmol/L in men and <1.3 mmol/L in women; 4) hypertension; and 5) fasting plasma glucose ≥5.6 mmol/L. A total of 118 patients were included. Among them, 69 patients (58%) had PTMS. The mean (± standard deviation) time from transplant was 59 ± 21 months (no significant difference in patients with or without metabolic syndrome). Overall, patients with metabolic syndrome had a significantly higher average age, posttransplantation body mass index, fasting glucose, high‐density lipoprotein levels, and serum triglycerides. There was no difference in creatinine, hemoglobin, or prednisone average dose between the 2 groups. There were 25 major vascular events affecting 21% of patients. There were significantly more vascular events in patients with metabolic syndrome posttransplantation than in those without (30% vs. 8%; P = 0.003) during the study period. In conclusion, the prevalence of metabolic syndrome post–liver transplant is significantly higher than that estimated in the general population. Metabolic syndrome appears to be associated with an increased risk of major vascular events in our liver transplant population. Liver Transpl 13:1109–1114, 2007.

Cyclosporin versus Tacrolimus as Primary Immunosuppressant After Liver Transplantation: A Meta-Analysis

A systematic review of randomized clinical trials (RCT) was undertaken to evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. MEDLINE, EMBASE, Cochrane Central and Hepato‐Biliary Group Controlled Trials Registers were searched. Using fixed and random effects model, relative risk (RR), values <1 favoring tacrolimus, with 95% confidence intervals (CI) were calculated. Of 717 potentially relevant references, 16 RCTs were eligible for inclusion. Mortality and graft loss at 1 year were significantly reduced in tacrolimus‐treated recipients (Death: RR 0.85, 95% CI 0.73–0.99; graft loss: RR 0.73, 95% CI 0.61–0.86). Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75–0.88) and steroid‐resistant rejection (RR 0.54, 95% CI 0.47–0.74) in the first year. Lymphoproliferative disorder or dialysis rates were not different but more de novo diabetes (RR 1.38, 95% CI 1.01–1.86) occurred with tacrolimus. More patients stopped cyclosporin than tacrolimus (RR 0.57, 95% CI 0.49–0.66). Treating 100 recipients with tacrolimus instead of cyclosporin would avoid rejection and steroid‐resistant rejection in nine and seven patients respectively, graft loss and death in five and two patients respectively, but four additional patients would develop diabetes after liver transplantation.

Is routine ureteric stenting needed in kidney transplantation? A randomized trial.

Background. Whether routine ureteric stenting in low-urological-risk patients reduces the risk of urological complications in kidney transplantation is not established. Methods. Eligible patients were recipients of single-organ renal transplants with normal lower urinary tracts. Patients were randomized intraoperatively to receive either routine stenting or stenting only in the event of technical difficulties with the anastomosis. All patients underwent Lich-Gregoire ureteroneocystostomy. Results. Between June 1994 and December 1997, 331 kidney transplants were performed at a single center, 305 patients were eligible, and 280 patients were enrolled and randomized. Donor and recipient age, sex, donor source, whether first or subsequent grafts, ureteric length, native renal disease, and immunosuppression were similar in each group. In the no-routine-stenting group 6 of 137 patients (4.4%) received stents after randomization for intraoperative events that in the surgeon’s opinion required use of a stent. In an intention-to-treat analysis there was no difference between groups in the primary outcome cluster of obstruction or leak [routine stenting 5 of 143 (3.5%) vs. no routine stenting 9 of 137 (6.6%);P =0.23], or in either of these complications analyzed separately. All urological complications were successfully managed without major morbidity. Living donor organs and shorter ureteric length (after trimming) were univariate risk factors for leaks, although increasing donor age was associated with obstruction. Conclusions. Routine ureteric stenting is unnecessary in kidney transplantation in patients at low risk for urological complications. Careful surgical technique with selective stenting of problematic anastomoses yields similar results.

Repopulation of liver endothelium by bone-marrow-derived cells

The mechanism underlying the immunological advantage of hepatic allografts relative to other organs is incompletely understood. We used molecular probes for the repetitive units on the Y chromosome, to identify an increasing number of male liver venous endothelial cells in needle biopsy samples of men who received female donor liver grafts. We have also shown repopulation of liver endothelium by bone marrow derived cells in a male to female mouse bone marrow transplant model. We conclude that the liver has unique venous endothelium characterised by turnover and replacement by bone marrow derived cells.

Conversion to rapamycin immunosuppression in renal transplant recipients : Report of an initial experience

Background. The aim of thisstudy is to evaluate the effects of RAPA conversion in patients undergoing cyclosporine (CsA) or tacrolimus (Tac) toxicity. Methods. Twenty renal transplant recipients were switched to fixed dose rapamycin (RAPA) (5 mg/day) 0 to 204 months posttransplant. Drug monitoring was not initially used to adjust doses. The indications for switch were chronic CsA or Tac nephrotoxicity (12), acute CsA or Tac toxicity (3), severe facial dysmorphism (2), posttransplant lymphoproliferative disorder (PTLD) in remission (2), and hepatotoxicity in 1. Follow-up is 7 to 24 months. Results. In the 12 patients switched because of chronic nephrotoxicity there was a significant decrease in serum creatinine [233±34 to 210±56 &mgr;mol/liter (P <0.05) at 6 months]. Facial dysmorphism improved in two patients. No relapse of PTLD was observed. Five patients developed pneumonia (two Pneumocystis carinii pneumonia, one infectious mononucleosis with polyclonal PTLD lung infiltrate) and two had bronchiolitis obliterans. There were no deaths. RAPA was discontinued in four patients, because of pneumonia in two, PTLD in one, and oral aphtous ulcers in one. RAPA levels were high (>15 ng/ml) in 7 of 13 (54%) patients. Conclusions. RAPA conversion provides adequate immunosuppression to enable CsA withdrawal. However, when converting patients to RAPA drug levels should be monitored to avoid over-immunosuppression and adequate antiviral and Pneumocystis carinii pneumonia prophylaxis should be given.

Prevention of experimental postoperative peritoneal adhesions by N,O-carboxymethyl chitosan

BACKGROUND Postsurgical adhesion formation can result in significant morbidity and, to a lesser extent, death. The purpose of this experiment was to assess the ability of N,O-carboxymethyl chitosan (NOCC) to prevent postsurgical adhesion formation in vivo. METHODS Randomized groups of Sprague-Dawley rats were studied under two abdominal surgery models, the uterine horn model and the small bowel laceration model, for the ability of NOCC to reduce the incidence and severity of adhesion formation. Adhesions in animals were assessed after death by a blinded observer 10 to 14 days after surgical manipulation. RESULTS NOCC consistently reduced the size, strength, and number of adhesions in both rat models. NOCC was also found to be more effective than hyaluronic acid at inhibiting adhesion formation. CONCLUSIONS NOCC is a more effective antiadhesion agent than is the more expensive hyaluronic acid. Although the exact mechanism of NOCCs antiadhesion activity is as yet unclear, the novel chemical is of particular interest for clinical use.

Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials.

Context:Benefits of recombinant activated factor VII (rFVIIa) in hemorrhage may be lost because of thromboembolic events (TAE). Method:MEDLINE, EMBASE, BIOSIS, CINAHL, Science Citation Index Expanded, clinicaltrials.gov were searched for placebo controlled trials of rFVIIa in patients without hemophilia. Reports of 22 randomized controlled trials were selected for analysis. Results were pooled using random effects models to calculate the odds ratios (OR) with 95% confidence interval (CI). Subgroup analyses were predetermined. Results:Among 3184 participants, 478 (15.0%) died and 249 (7.8%) had TAE. Additional blood transfusion was required in 517 (41.2%) of 1256 subjects. Patients receiving rFVIIa were less likely to need additional blood transfusions (OR, 0.54; 95% CI, 0.34–0.86) than patients receiving placebo. Mortality was not increased but may be reduced (OR, 0.88; 95% CI, 0.71–1.09). Reduction in mortality was more likely if rFVIIa was given therapeutically (OR, 0.87; 95% CI, 0.70–1.09) rather than prophylactically (OR, 1.00; 95% CI, 0.37–2.68). Differences in the pooled analysis of TAE were not statistically significant (OR, 1.17; 95% CI, 0.87–1.58) but the incidence of arterial TAE was likely higher in patients receiving rFVIIa (OR, 1.50; 95% CI, 0.93–2.41) although no differences were seen with respect to venous TAE (OR, 0.76; 95% CI, 0.49–1.15). Conclusions:Use of rFVIIa reduces the need for blood transfusion and it may reduce mortality, especially if the dose of rFVIIa is limited to therapeutic doses of 90 μg/kg. It does not increase the risk of venous thrombosis but it may increase the risk of arterial thrombosis.

A Clinical Pharmacokinetic Study of Tacrolimus and Sirolimus Combination Immunosuppression Comparing Simultaneous to Separated Administration

The pharmacokinetic (PK) interaction between tacrolimus (TAC) and sirolimus (SRL), similarly structured immunosuppressive compounds that share binding proteins, is unknown. The combination of SRL with cyclosporin (CsA) has been studied, and a 4-hour interval between dosing of the two drugs is recommended even though it is inconvenient for patients and may affect compliance. Twenty-five liver and kidney–pancreas transplant recipients treated with a combination of SRL and low-dose TAC completed full PK studies while being treated with 4-hour interval dosing (ID) and then with simultaneous dosing. Whole blood was sampled for immunoassay measurement of TAC and SRL levels. Blood concentration/dose ratios of SRL and TAC varied between patients by a factor of 8 and 5, respectively, but correlation between trough concentration levels (C0) and drug exposure area under the concentration–time curve (AUC) was excellent (TAC: r2 = 0.82; SRL: r2 = 0.83). Neither PK profiles of SRL nor those of TAC were altered by simultaneous administration. Dose-corrected AUC and C0 of TAC correlated with SRL (r2 = 0.8 and 0.8, respectively). Bone marrow suppression and nephrotoxicity were not enhanced nor were any new toxicities observed when TAC and SRL were used in combination. These data confirm that simultaneous dosing of TAC and SRL after transplantation is safe and that trough level monitoring is adequate to control therapy.